Pyrazole derivative manufacturing method

ABSTRACT

The present invention provides a method for manufacturing a compound represented by formula (I). With this method, provided are a method for manufacturing a 4-heteroaryl-N-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxylic acid amide derivative; and an intermediate for this manufacturing method.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Divisional of copending application Ser. No.15/840,858, filed on Dec. 13, 2017, which is a Divisional of applicationSer. No. 15/329,447, filed on Jan. 26, 2017, which is the National Phaseunder 35 U.S.C. § 371 of International Application No.PCT/JP2015/071536, filed on Jul. 29, 2015, which claims the benefitunder 35 U.S.C. § 119(a) to Patent Application No. 2014-155538, filed inJapan on Jul. 30, 2014 and Patent Application No. 2014-189458, filed inJapan on Sep. 17, 2014, all of which are hereby expressly incorporatedby reference into the present application.

TECHNICAL FIELD

The present invention relates to a method for manufacturing a4-heteroaryl-N-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxylicacid amide derivative represented by formula (I), which exhibitsphosphodiesterase 10 (hereinafter shown as “PDE10”) inhibitory activity;and an intermediate for this manufacturing method.

BACKGROUND ART

A4-heteroaryl-N-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxylicacid amide derivative represented by formula (I) exhibits excellentPDE10 inhibitory activity, is useful for treating and/or preventing avariety of symptoms of mental disorders linked to PDE10 (for example,paranoid type, disorganized type, catatonic type, undifferentiated andresidual type schizophrenia, and the like), and has potential as atherapeutic agent having diminished adverse reactions.

As a method for manufacturing anN-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxylic acidamide derivative (formula (i)), scheme 1 on page 26 of WO 2012/076430(PTL 1) discloses a manufacturing method in which a carboxylic acidderivative (formula (ii)) and a 7-amino-[1,2,4]triazolo[1,5-a]pyridinederivative (formula (iii)) are subjected to a condensation reaction.

As a method for manufacturing a4-heteroaryl-N-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxylicacid amide derivative (formula (I-a)), page 184 of WO 2014/133046 (PTL2) discloses a manufacturing method in which a carboxylic acidderivative (formula (CA)) and a 7-amino-[1,2,4]triazolo[1,5-a]pyridinederivative (formula (AM)) are subjected to a condensation reaction.

According to PTL 1, a compound represented by formula (iii) ismanufactured using O-(mesitylsulfonyl)hydroxylamine (formula (v)).

A compound represented by formula (I) in the present invention can bemanufactured using a compound represented by formula (iii) disclosed inPTL 1, but in cases where a compound represented by formula (iii) ismanufactured according to the manufacturing method disclosed in PTL 1,it is essential to use the compound represented by formula (v). However,it has been pointed out that the compound represented by formula (v) isnot suitable for use in large scale synthesis or industrialmanufacturing due to problems relating to the stability and safety ofthe compound (see NPL 1). Therefore, in cases where large scalesynthesis or industrial manufacturing of a compound represented byformula (I) is being considered, it is essential to find a novelmanufacturing method that is different from the manufacturing methoddisclosed in PTL 1.

Meanwhile, a method for manufacturing an analogous compound to formula(iii) (formula (iii-1)) is disclosed in WO 2013/117610 (PTL 3). However,the yield of a compound having a R^(V)═NH₂ group is low, at 28%, andthere are no synthesis examples of 6,7-2 substituted[1,2,4]triazolo[1,5-a]pyridine derivatives.

In addition, no manufacturing method is known whereby a6-fluoro-7-amino-4-phenyl-[1,2,4]triazolo[1,5-a]pyridine derivative,which is a partial structure of a4-heteroaryl-N-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxylicacid amide derivative represented by formula (I), can be synthesized inlarge quantities with good efficiency.

Therefore, there is a need to overcome these problems and establish anefficient manufacturing method that is suitable for large scalesynthesis or industrial manufacturing of a compound represented byformula (I).

CITATION LIST Patent Literature

-   [PTL 1] WO 2012/076430-   [PTL 2] WO 2014/133046-   [PTL 3] WO 2013/117610

Non Patent Literature

-   [NPL 1] Organic Process Research & Development, 13, pages 263-267,    2009.

SUMMARY OF INVENTION Technical Problem

The purpose of the present invention is to provide an efficientmanufacturing method that is suitable for large scale synthesis orindustrial manufacturing of a4-heteroaryl-N-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxylicacid amide derivative represented by formula (I), and especially a novelmanufacturing method by which a compound represented by formula (I) ismanufactured without using a 7-amino-[1,2,4]triazolo[1,5-a]pyridinederivative represented by formula (iii) when obtaining this derivativein large scale or industrial manufacturing; and an intermediate that isuseful for this manufacturing method.

Solution to Problem

The inventors of the present invention have carried out diligentresearch in order to solve this problem. As a result, the inventors ofthe present invention found a method for easily manufacturing a4-heteroaryl-N-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxylicacid amide derivative represented by formula (I) below in a shortprocess and with a good yield, and thereby completed the presentinvention on the basis of these findings.

(The definitions of p, q, R¹, R², R³, R⁴ and ring A group in formula (I)are explained in mode [1] below.)

Advantageous Effects of Invention

The present invention is a method for manufacturing a4-heteroaryl-N-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxylicacid amide derivative represented by formula (I) below, which exhibitsPDE10 inhibitory activity; and an intermediate that is useful for thismanufacturing method. The present invention can provide a manufacturingmethod which has a good yield and a short process and is simple andindustrially advantageous, and is industrially useful.

DESCRIPTION OF EMBODIMENTS Modes of the Present Invention

The present invention is a method for manufacturing a4-heteroaryl-N-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxylicacid amide derivative represented by formula (I), which is illustratedin the modes below; and an intermediate that is useful for thismanufacturing method, and is described below.

[1] A first mode of the present invention is a method for manufacturinga compound represented by formula (I) below:

[in formula (I), p denotes an integer between 0 and 3; q denotes aninteger between 0 and 2; R¹ s independently denote a group arbitrarilyselected from among a halogen atom, a cyano group, a C₁₋₆ alkyl group, ahalogenated C₁₋₆ alkyl group and a C₁₋₆ alkoxy group; R² denotes a C₁₋₆alkyl group; R³ denotes a group arbitrarily selected from among ahydrogen atom and a fluorine atom; R⁴ groups each independently denote agroup arbitrarily selected from among a halogen atom, a C₁₋₆ alkyl groupand a C₁₋₆ alkoxy group; and ring A group represented by formula (II):

denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarilyselected from among a pyridin-2-yl group, a pyridazin-3-yl group, apyrimidin-2-yl group, a pyrimidin-4-yl group and a pyrazin-2-yl group],the manufacturing method including stages in which a compoundrepresented by formula (ET-1):

[in formula (ET-1), p, R¹, R² and ring A group represented by formula(II) are defined in the same way as for formula (I) in mode [1]; R^(D)denotes a group arbitrarily selected from among a C₁₋₆ alkyl group, aC₆₋₁₄ aryl group and a C₇₋₂₀ aralkyl group (a routine method formanufacturing a compound represented by formula (ET-1) is describedlater)] and an aqueous ammonia solution are reacted with each other at atemperature between 0° C. and a temperature at which the reactionsolution refluxes, thereby obtaining a compound represented by formula(AD-1):

[in formula (AD-1), p, R¹, R² and ring A group represented by formula(II) are defined in the same way as for formula (I) in mode [1]] (stage[1]-1), the compound represented by formula (AD-1) and a2-amino-4-iodopyridine derivative represented by formula (PY-1):

[in formula (PY-1), R³ denotes a group arbitrarily selected from among ahydrogen atom and a fluorine atom (a routine method for manufacturing acompound represented by formula (PY-1) is described later)] are reactedwith each other in the presence of N,N-dimethyl-1,2-ethanediamine,copper iodide and an inorganic base such as potassium carbonate orpotassium phosphate using a solvent which does not take part in thereaction, such as 1,4-dioxane, tetrahydrofuran or 1,2-dimethoxyethane,at a temperature between 0° C. and a temperature at which the solventrefluxes, thereby obtaining a compound represented by formula (AD-2):

[in formula (AD-2), p, R¹, R², R³ and ring A group represented byformula (II) are defined in the same way as for formula (I) in mode [1]](stage [1]-2), the compound represented by formula (AD-2) and a compoundrepresented by formula (IM-1):

[in formula (IM-1), q and R⁴ are defined in the same way as for formula(I) above; and R^(B) denotes a C₁₋₆ alkyl group] or a salt thereof (thecompound represented by formula (IM-1) and salt thereof are commerciallyavailable compounds or compounds that can be easily obtained fromcommercially available compounds using manufacturing methods known fromliterature) are reacted with each other using a solvent which does nottake part in the reaction, such as dimethyl sulfoxide or pyridine, at atemperature between 0° C. and a temperature at which the solventrefluxes, thereby obtaining a compound represented by formula (AD-3):

[in formula (AD-3), p, q, R¹, R², R³, R⁴ and ring A group represented byformula (II) are defined in the same way as for formula (I) in mode [1]](stage [1]-3), and the compound represented by formula (AD-3) issubjected to a cyclization reaction in the presence of air using asolvent which does not take part in the reaction, such as dimethylsulfoxide (DMSO) or N-methylpyrrolidone (NMP), at a temperature between0° C. and a temperature at which the solvent refluxes in the presence ofa copper reagent such as copper iodide (CuI) or copper chloride (CuCl)(stage [1]-4), thereby obtaining the compound represented by formula(I).

[1-1] A preferred aspect of mode [1] is a method in which a compoundrepresented by formula (I) above is manufactured [in formula (I), p, q,R³ and ring A group represented by formula (II) are defined in the sameway as for mode [1] above; R¹ denotes a group arbitrarily selected fromamong a fluorine atom, a chlorine atom, a cyano group, a methyl group, atrifluoromethyl group and a methoxy group; R² denotes a methyl group;and R⁴ denotes a group arbitrarily selected from among a fluorine atom,a methyl group and a methoxy group], the manufacturing method includingstages in which a compound represented by formula (I) is obtained [thesestages are the same as (stage [1]-1) to (stage [1]-4) in mode [1] above;the definitions of the substituent groups in the intermediates in (stage[1]-1) to (stage [1]-4) are the same as the definitions in mode [1-1],and R^(B) in formula (IM-1) is a C₁₋₆ alkyl group].

[1-2] A more preferred aspect of mode [1] is a method in which acompound represented by formula (I) above is manufactured [in formula(I), p, R¹, R², R⁴ and ring A group represented by formula (II) aredefined in the same way as for mode [1-1] above; q denotes the integer0; and R³ denotes a fluorine atom], the manufacturing method includingstages in which a compound represented by formula (I) is obtained [thesestages are the same as (stage [1]-1) to (stage [1]-4) in mode [1] above;the definitions of the substituent groups in the intermediates in (stage[1]-1) to (stage [1]-4) are the same as the definitions in mode [1-2],and R^(B) in formula (IM-1) is a C₁₋₆ alkyl group].

[1-3] A yet more preferred aspect of mode [1] is a method in which acompound represented by formula (I) above is manufactured [in formula(I), p, q, R¹, R², R³ and R⁴ are defined in the same way as for mode[1-2] above; ring A group represented by formula (II) is apyrimidin-4-yl group; and a more specific group obtained by combiningthe definitions of p, R¹ and ring A group represented by formula (II) isa 2,5-dimethylpyrimidin-4-yl group], the manufacturing method includingstages in which a compound represented by formula (I) is obtained [thesestages are the same as (stage [1]-1) to (stage [1]-4) in mode [1] above;the definitions of the substituent groups in the intermediates in (stage[1]-1) to (stage [1]-4) are the same as the definitions in mode [1-3],and R^(B) in formula (IM-1) is a C₁₋₆ alkyl group].

[1a] Another aspect of the first mode of the present invention is amethod for manufacturing a compound represented by formula (I) below:

[in formula (I), p denotes an integer between 0 and 3; q denotes aninteger between 0 and 2; R¹ groups each independently denote a grouparbitrarily selected from among a halogen atom, a cyano group, a C₁₋₆alkyl group, a C₃₋₈ cycloalkyl group, a halogenated C₁₋₆ alkyl group, aC₂₋₆ alkenyl group, a C₁₋₆ alkoxy group, a C₁₋₆ alkoxy-C₁₋₆ alkyl group,a hydroxy-C₁₋₆ alkyl group and a C₂₋₇ alkanoyl group; R² denotes a C₁₋₆alkyl group; R³ denotes a group arbitrarily selected from among ahydrogen atom and a fluorine atom; R⁴ groups each independently denote agroup arbitrarily selected from among a halogen atom, a C₁₋₆ alkyl groupand a C₁₋₆ alkoxy group; and ring A group represented by formula (II):

denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarilyselected from among a thiazol-2-yl group, a thiazol-4-yl group, a1-methyl-1H-imidazol-4-yl group, a 1,3,4-thiadiazol-2-yl group, a1,2,4-thiadiazol-5-yl group, a pyridin-2-yl group, a pyridazin-3-ylgroup, a pyrimidin-2-yl group, a pyrimidin-4-yl group and a pyrazin-2-ylgroup], the manufacturing method including stages in which a compoundrepresented by formula (ET-1):

[in formula (ET-1), p, R¹, R² and ring A group represented by formula(II) are defined in the same way as for formula (I) in mode [1a]; R^(D)denotes a group arbitrarily selected from among a C₁₋₆ alkyl group, aC₆₋₁₄ aryl group and a C₇₋₂₀ aralkyl group (a routine method formanufacturing a compound represented by formula (ET-1) is describedlater)] and an aqueous ammonia solution are reacted with each other at atemperature between 0° C. and a temperature at which the reactionsolution refluxes, thereby obtaining a compound represented by formula(AD-1):

[in formula (AD-1), p, R¹, R² and ring A group represented by formula(II) are defined in the same way as for formula (I) in mode [1a]] (stage[1a]-1), the compound represented by formula (AD-1) and a2-amino-4-iodopyridine derivative represented by formula (PY-1):

[in formula (PY-1), R³ denotes a group arbitrarily selected from among ahydrogen atom and a fluorine atom (a routine method for manufacturing acompound represented by formula (PY-1) is described later)] are reactedwith each other in the presence of N,N-dimethyl-1,2-ethanediamine,copper iodide (CuI) and an inorganic base such as potassium carbonate orpotassium phosphate using a solvent which does not take part in thereaction, such as 1,4-dioxane, tetrahydrofuran or 1,2-dimethoxyethane,at a temperature between 0° C. and a temperature at which the solventrefluxes, thereby obtaining a compound represented by formula (AD-2):

[in formula (AD-2), p, R¹, R², R³ and ring A group represented byformula (II) are defined in the same way as for formula (I) in mode[1a]] (stage [1a]-2), the compound represented by formula (AD-2) and acompound represented by formula (IM-1):

[in formula (IM-1), q and R⁴ are defined in the same way as for formula(I) in mode [1a]; and R^(B) denotes a C₁₋₆ alkyl group] or a saltthereof (the compound represented by formula (IM-1) and salt thereof arecommercially available compounds or compounds that can be easilyobtained from commercially available compounds using manufacturingmethods known from literature) are reacted with each other using asolvent which does not take part in the reaction, such as dimethylsulfoxide or pyridine, at a temperature between 0° C. and a temperatureat which the solvent refluxes, thereby obtaining a compound representedby formula (AD-3):

[in formula (AD-3), p, q, R¹, R², R³, R⁴ and ring A group represented byformula (II) are defined in the same way as for formula (I) in mode[1a]] (stage [1a]-3), and the compound represented by formula (AD-3) issubjected to a cyclization reaction in the presence of air using asolvent which does not take part in the reaction, such as dimethylsulfoxide (DMSO) or N-methylpyrrolidone (NMP), at a temperature between0° C. and a temperature at which the solvent refluxes in the presence ofa copper reagent such as copper iodide (CuI) or copper chloride (CuCl)(stage [1a]-4), thereby obtaining the compound represented by formula(I).

[1a-1] A preferred aspect of mode [1a] is a method in which a compoundrepresented by formula (I) above is manufactured [in formula (I), p, q,R³ and ring A group represented by formula (II) are defined in the sameway as in mode [1a] above; R¹ denotes a group arbitrarily selected fromamong a fluorine atom, a chlorine atom, a bromine atom, a cyano group, amethyl group, an ethyl group, an isopropyl group, a tert-butyl group, acyclopropyl group, a difluoromethyl group, a trifluoromethyl group, a1-hydroxyethyl group, a vinyl group, an acetyl group, a methoxy groupand an ethoxyethyl group; R² denotes a methyl group; and R⁴ denotes agroup arbitrarily selected from among a fluorine atom, a methyl groupand a methoxy group], the manufacturing method including stages in whicha compound represented by formula (I) is obtained [these stages are thesame as (stage [1a]-1) to (stage [1a]-4) in mode [1a] above; thedefinitions of the substituent groups in the intermediates in (stage[1a]-1) to (stage [1a]-4) are the same as the definitions in mode[1a-1], and R^(B) in formula (IM-1) is a C₁₋₆ alkyl group].

[1a-2] A more preferred aspect of mode [1a] is a method in which acompound represented by formula (I) above is manufactured [in formula(I), p, R¹, R², R⁴ and ring A group represented by formula (II) aredefined in the same way as for mode [1a-1] above; q denotes the integer0; and R³ denotes a fluorine atom], the manufacturing method includingstages in which a compound represented by formula (I) is obtained [thesestages are the same as (stage [1a]-1) to (stage [1a]-4) in mode [1a]above; the definitions of the substituent groups in the intermediates in(stage [1a]-1) to (stage [1a]-4) are the same as the definitions in mode[1a-2], and R^(B) in formula (IM-1) is a C₁₋₆ alkyl group].

[1a-3] A yet more preferred aspect of mode [1a] is a method in which acompound represented by formula (I) above is manufactured [in formula(I), p, q, R¹, R², R³ and R⁴ are defined in the same way as for mode[1a-2] above; ring A group represented by formula (II) is a thiazol-2-ylgroup or a pyrimidin-4-yl group; and a more specific group obtained bycombining the definitions of p, R¹ and ring A group represented byformula (II) is a 4-(trifluoromethyl)thiazol-2-yl group, a5-fluoro-2-methoxypyrimidin-4-yl group, a 2,5-dimethylpyrimidin-4-ylgroup or a 2-methylpyrimidin-4-yl group], the manufacturing methodincluding stages in which a compound represented by formula (I) isobtained [these stages are the same as (stage [1a]-1) to (stage [1a]-4)in mode [1a] above; the definitions of the substituent groups in theintermediates in (stage [1a]-1) to (stage [1a]-4) are the same as thedefinitions in mode [1a-3], and R^(B) in formula (IM-1) is a C₁₋₆ alkylgroup].

[2] A second mode of the present invention is formula (AD-2) below:

[in formula (AD-2), p denotes an integer between 0 and 3; R¹ groups eachindependently denote a group arbitrarily selected from among a halogenatom, a cyano group, a C₁₋₆ alkyl group, a halogenated C₁₋₆ alkyl groupand a C₁₋₆ alkoxy group; R² denotes a C₁₋₆ alkyl group; R³ denotes agroup arbitrarily selected from among a hydrogen atom and a fluorineatom; and ring A group represented by formula (II):

denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarilyselected from among a pyridin-2-yl group, a pyridazin-3-yl group, apyrimidin-2-yl group, a pyrimidin-4-yl group and a pyrazin-2-yl group],the manufacturing method including stages in which a compoundrepresented by formula (ET-1):

[in formula (ET-1), p, R¹, R² and ring A group represented by formula(II) are defined in the same way as for formula (AD-2) in mode [2];R^(D) denotes a group arbitrarily selected from among a C₁₋₆ alkylgroup, a C₆₋₁₄ aryl group and a C₇₋₂₀ aralkyl group (a routine methodfor manufacturing a compound represented by formula (ET-1) is describedlater)] and an aqueous ammonia solution are reacted with each other at atemperature between 0° C. and a temperature at which the reactionsolution refluxes, thereby obtaining a compound represented by formula(AD-1):

[in formula (AD-1), p, R¹, R² and ring A group represented by formula(II) are defined in the same way as for formula (AD-2) in mode [2]](stage [2]-1), and the compound represented by formula (AD-1) and a2-amino-4-iodopyridine derivative represented by formula (PY-1):

[in formula (PY-1), R³ denotes a hydrogen atom or a fluorine atom (aroutine method for manufacturing a compound represented by formula(PY-1) is described later)] are reacted with each other in the presenceof N,N-dimethyl-1,2-ethanediamine, copper iodide and an inorganic basesuch as potassium carbonate or potassium phosphate using a solvent whichdoes not take part in the reaction, such as 1,4-dioxane, tetrahydrofuranor 1,2-dimethoxyethane, at a temperature between 0° C. and a temperatureat which the solvent refluxes, thereby obtaining a compound representedby formula (AD-2) (stage [2]-2).

[2-1] A preferred aspect of mode [2] is a method in which a compoundrepresented by formula (AD-2) above is manufactured [in formula (AD-2),p, R³ and ring A group represented by formula (II) are defined in thesame way as in mode [2] above; R¹ denotes a group arbitrarily selectedfrom among a fluorine atom, a chlorine atom, a cyano group, a methylgroup, a trifluoromethyl group and a methoxy group; and R² denotes amethyl group], the manufacturing method including stages in which acompound represented by formula (AD-2) is obtained [these stages are thesame as (stage [2]-1) and (stage [2]-2) in mode [2] above; and thedefinitions of the substituent groups in the intermediates in (stage[2]-1) and (stage [2]-2) are the same as the definitions in mode [2-1]].

[2-2] A more preferred aspect of mode [2] is a method in which acompound represented by formula (AD-2) above is manufactured [in formula(AD-2), p, R¹, R² and ring A group represented by formula (II) aredefined in the same way as in mode [2-1] above; and R³ denotes afluorine atom], the manufacturing method including stages in which acompound represented by formula (AD-2) is obtained [these stages are thesame as (stage [2]-1) and (stage [2]-2) in mode [2] above; and thedefinitions of the substituent groups in the intermediates in (stage[2]-1) and (stage [2]-2) are the same as the definitions in mode [2-2]].

[2-3] A yet more preferred aspect of mode [2] is a method in which acompound represented by formula (AD-2) above is manufactured [in formula(AD-2), p, R¹, R² and R³ are defined in the same way as for mode [2-2]above; ring A group represented by formula (II) is a pyrimidin-4-ylgroup; and a more specific group obtained by combining the definitionsof p, R¹ and ring A group represented by formula (II) is a2,5-dimethylpyrimidin-4-yl group], the manufacturing method includingstages in which a compound represented by formula (AD-2) is obtained[these stages are the same as (stage [2]-1) and (stage [2]-2) in mode[2] above; and the definitions of the substituent groups in theintermediates in (stage [2]-1) and (stage [2]-2) are the same as thedefinitions in mode [2-3]].

[2a] Another aspect of the second mode of the present invention is amethod for manufacturing a compound represented by formula (AD-2) below:

[in formula (AD-2), p denotes an integer between 0 and 3; R¹ groups eachindependently denote a group arbitrarily selected from among a halogenatom, a cyano group, a C₁₋₆ alkyl group, a C₃₋₈ cycloalkyl group, ahalogenated C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₁₋₆ alkoxy group,a C₁₋₆ alkoxy-C₁₋₆ alkyl group, a hydroxy-C₁₋₆ alkyl group and a C₂₋₇alkanoyl group; R² denotes a C₁₋₆ alkyl group; R³ denotes a grouparbitrarily selected from among a hydrogen atom and a fluorine atom; andring A group represented by formula (II):

denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarilyselected from among a thiazol-2-yl group, a thiazol-4-yl group, a1-methyl-1H-imidazol-2-yl group, a 1,3,4-thiadiazol-2-yl group, a1,2,4-thiadiazol-5-yl group, a pyridin-2-yl group, a pyridazin-3-ylgroup, a pyrimidin-2-yl group, a pyrimidin-4-yl group and a pyrazin-2-ylgroup], the manufacturing method including stages in which a compoundrepresented by formula (ET-1):

[in formula (ET-1), p, R¹, R² and ring A group represented by formula(II) are defined in the same way as for formula (AD-2) in mode [2a];R^(D) denotes a group arbitrarily selected from among a C₁₋₆ alkylgroup, a C₆₋₁₄ aryl group and a C₇₋₂₀ aralkyl group (a routine methodfor manufacturing a compound represented by formula (ET-1) is describedlater)] and an aqueous ammonia solution are reacted with each other at atemperature between 0° C. and a temperature at which the reactionsolution refluxes, thereby obtaining a compound represented by formula(AD-1):

[in formula (AD-1), p, R¹, R² and ring A group represented by formula(II) are defined in the same way as for formula (AD-2) in mode [2a]](stage [2a]-1), and the compound represented by formula (AD-1) and a2-amino-4-iodopyridine derivative represented by formula (PY-1):

[in formula (PY-1), R³ denotes a hydrogen atom or a fluorine atom (aroutine method for manufacturing a compound represented by formula(PY-1) is described later)] are reacted with each other in the presenceof N,N-dimethyl-1,2-ethanediamine, copper iodide (CuI) and an inorganicbase such as potassium carbonate or potassium phosphate using a solventwhich does not take part in the reaction, such as 1,4-dioxane,tetrahydrofuran or 1,2-dimethoxyethane, at a temperature between 0° C.and a temperature at which the solvent refluxes, thereby obtaining thecompound represented by formula (AD-2) (stage [2a]-2).

[2a-1] A preferred aspect of mode [2a] is a method in which a compoundrepresented by formula (AD-2) above is manufactured [in formula (AD-2),p, R³ and ring A group represented by formula (II) are defined in thesame way as in mode [2a] above; R¹ denotes a group arbitrarily selectedfrom among a fluorine atom, a chlorine atom, a bromine atom, a cyanogroup, a methyl group, an ethyl group, an isopropyl group, a tert-butylgroup, a cyclopropyl group, a difluoromethyl group, a trifluoromethylgroup, a 1-hydroxyethyl group, a vinyl group, an acetyl group, a methoxygroup and an ethoxyethyl group; and R² denotes a methyl group], themanufacturing method including stages in which a compound represented byformula (AD-2) is obtained [these stages are the same as (stage [2a]-1)and (stage [2a]-2) in mode [2a] above; and the definitions of thesubstituent groups in the intermediates in (stage [2a]-1) and (stage[2a]-2) are the same as the definitions in mode [2a-1]].

[2a-2] A more preferred aspect of mode [2a] is a method in which acompound represented by formula (AD-2) above is manufactured [in formula(AD-2), p, R¹, R² and ring A group represented by formula (II) aredefined in the same way as in mode [2a-1] above; and R³ denotes afluorine atom], the manufacturing method including stages in which acompound represented by formula (AD-2) is obtained [these stages are thesame as (stage [2a]-1) and (stage [2a]-2) in mode [2a] above; and thedefinitions of the substituent groups in the intermediates in (stage[2a]-1) and (stage [2a]-2) are the same as the definitions in mode[2a-2]].

[2a-3] A yet more preferred aspect of mode [2a] is a method in which acompound represented by formula (AD-2) above is manufactured [in formula(AD-2), p, R¹, R² and R³ are defined in the same way as for mode [2a-2]above; ring A group represented by formula (II) is a thiazol-2-yl groupor a pyrimidin-4-yl group; and a more specific group obtained bycombining the definitions of p, R¹ and ring A group represented byformula (II) is a 4-(trifluoromethyl)thiazol-2-yl group, a5-fluoro-2-methoxypyrimidin-4-yl group, a 2,5-dimethylpyrimidin-4-ylgroup or a 2-methylpyrimidin-4-yl group], the manufacturing methodincluding stages in which a compound represented by formula (AD-2) isobtained [these stages are the same as (stage [2a]-1) and (stage [2a]-2)in mode [2a] above; and the definitions of the substituent groups in theintermediates in (stage [2a]-1) and (stage [2a]-2) are the same as thedefinitions in mode [2a-3]].

[3] A third mode of the present invention is a method for manufacturinga compound represented by formula (AD-2) below:

[in formula (AD-2), p denotes an integer between 0 and 3; R¹ groups eachindependently denote a group arbitrarily selected from among a halogenatom, a cyano group, a C₁₋₆ alkyl group, a halogenated C₁₋₆ alkyl groupand a C₁₋₆alkoxy group; R² denotes a C₁₋₆ alkyl group; R³ denotes agroup arbitrarily selected from among a hydrogen atom and a fluorineatom; and ring A group represented by formula (II):

denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarilyselected from among a pyridin-2-yl group, a pyridazin-3-yl group, apyrimidin-2-yl group, a pyrimidin-4-yl group and a pyrazin-2-yl group],the manufacturing method including a stage in which a compoundrepresented by formula (AD-1):

[in formula (AD-1), p, R¹, R² and ring A group represented by formula(II) are defined in the same way as for formula (AD-2) in mode [3]] anda 2-amino-4-iodopyridine derivative represented by formula (PY-1):

[in formula (PY-1), R³ denotes a hydrogen atom or a fluorine atom (aroutine method for manufacturing a compound represented by formula(PY-1) is described later)] are reacted with each other in the presenceof N,N-dimethyl-1,2-ethanediamine, copper iodide (CuI) and an inorganicbase such as potassium carbonate or potassium phosphate using a solventwhich does not take part in the reaction, such as 1,4-dioxane,tetrahydrofuran or 1,2-dimethoxyethane, at a temperature between 0° C.and a temperature at which the solvent refluxes, thereby obtaining thecompound represented by formula (AD-2) (stage [3]-1).

[3-1] A preferred aspect of mode [3] is a method in which a compoundrepresented by formula (AD-2) above is manufactured [in formula (AD-2),p, R³ and ring A group represented by formula (II) are defined in thesame way as in mode [3] above; R¹ denotes a group arbitrarily selectedfrom among a fluorine atom, a chlorine atom, a cyano group, a methylgroup, a trifluoromethyl group and a methoxy group; and R² denotes amethyl group], the manufacturing method including a stage in which acompound represented by formula (AD-2) is obtained [this stage is thesame as (stage [3]-1) in mode [3] above; and the definitions of thesubstituent groups in the intermediate in (stage [3]-1) are the same asthe definitions in mode [3-1]].

[3-2] A more preferred aspect of mode [3] is a method in which acompound represented by formula (AD-2) above is manufactured [in formula(AD-2), p, R¹, R² and ring A group represented by formula (II) aredefined in the same way as in mode [3-1] above; and R³ denotes afluorine atom], the manufacturing method including a stage in which acompound represented by formula (AD-2) is obtained [this stage is thesame as (stage [3]-1) in mode [3] above; and the definitions of thesubstituent groups in the intermediate in (stage [3]-1) are the same asthe definitions in mode [3-2]1].

[3-3] A yet more preferred aspect of mode [3] is a method in which acompound represented by formula (AD-2) above is manufactured [in formula(AD-2), p, R¹, R² and R³ are defined in the same way as for mode [3-2]above; ring A group represented by formula (II) is a pyrimidin-4-ylgroup; and a more specific group obtained by combining the definitionsof p, R¹ and ring A group represented by formula (II) is a2,5-dimethylpyrimidin-4-yl group], the manufacturing method including astage in which a compound represented by formula (AD-2) is obtained[this stage is the same as (stage [3]-1) in mode [3] above; and thedefinitions of the substituent groups in the intermediate in (stage[3]-1) are the same as the definitions in mode [3-3]].

[3a] Another aspect of the third mode of the present invention is amethod for manufacturing a compound represented by formula (AD-2) below:

[in formula (AD-2), p denotes an integer between 0 and 3; R¹ groups eachindependently denote a group arbitrarily selected from among a halogenatom, a cyano group, a C₁₋₆ alkyl group, a C₃₋₈ cycloalkyl group, ahalogenated C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₁₋₆ alkoxy group,a C₁₋₆ alkoxy-C₁₋₆ alkyl group, a hydroxy-C₁₋₆ alkyl group and a C₂₋₇alkanoyl group; R² denotes a C₁₋₆ alkyl group; R³ denotes a grouparbitrarily selected from among a hydrogen atom and a fluorine atom; andring A group represented by formula (II):

denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarilyselected from among a thiazol-2-yl group, a thiazol-4-yl group, a1-methyl-1H-imidazol-4-yl group, a 1,3,4-thiadiazol-2-yl group, a1,2,4-thiadiazol-5-yl group, a pyridin-2-yl group, a pyridazin-3-ylgroup, a pyrimidin-2-yl group, a pyrimidin-4-yl group and a pyrazin-2-ylgroup], the manufacturing method including a stage in which a compoundrepresented by formula (AD-1):

[in formula (AD-1), p, R¹, R² and ring A group represented by formula(II) are defined in the same way as for formula (AD-2) in mode [3a]] anda 2-amino-4-iodopyridine derivative represented by formula (PY-1):

[in formula (PY-1), R³ denotes a hydrogen atom or a fluorine atom (aroutine method for manufacturing a compound represented by formula(PY-1) is described later)] are reacted with each other in the presenceof N,N-dimethyl-1,2-ethanediamine, copper iodide and an inorganic basesuch as potassium carbonate or potassium phosphate using a solvent whichdoes not take part in the reaction, such as 1,4-dioxane, tetrahydrofuranor 1,2-dimethoxyethane, at a temperature between 0° C. and a temperatureat which the solvent refluxes, thereby obtaining the compoundrepresented by formula (AD-2) (stage [3a]-1).

[3a-1] A preferred aspect of mode [3a] is a method in which a compoundrepresented by formula (AD-2) above is manufactured [in formula (AD-2),p, R³ and ring A group represented by formula (II) are defined in thesame way as in mode [3a] above; R¹ denotes a group arbitrarily selectedfrom among a fluorine atom, a chlorine atom, a bromine atom, a cyanogroup, a methyl group, an ethyl group, an isopropyl group, a tert-butylgroup, a cyclopropyl group, a difluoromethyl group, a trifluoromethylgroup, a 1-hydroxyethyl group, a vinyl group, an acetyl group, a methoxygroup and an ethoxyethyl group; and R² denotes a methyl group], themanufacturing method including a stage in which a compound representedby formula (AD-2) is obtained [this stage is the same as (stage [3a]-1)in mode [3a] above; and the definitions of the substituent groups in theintermediate in (stage [3a]-1) are the same as the definitions in mode[3a-1]].

[3a-2] A more preferred aspect of mode [3a] is a method in which acompound represented by formula (AD-2) above is manufactured [in formula(AD-2), p, R¹, R² and ring A group represented by formula (II) aredefined in the same way as in mode [3a-1] above; and R³ denotes afluorine atom], the manufacturing method including a stage in which acompound represented by formula (AD-2) is obtained [this stage is thesame as (stage [3a]-1) in mode [3a] above; and the definitions of thesubstituent groups in the intermediate in (stage [3a]-1) are the same asthe definitions in mode [3a-2]].

[3a-3] A yet more preferred aspect of mode [3a] is a method in which acompound represented by formula (AD-2) above is manufactured [in formula(AD-2), p, R¹, R² and R³ are defined in the same way as for mode [3a-2]above; ring A group represented by formula (II) is a thiazol-2-yl groupor a pyrimidin-4-yl group; and a more specific group obtained bycombining the definitions of p, R¹ and ring A group represented byformula (II) is a 4-(trifluoromethyl)thiazol-2-yl group, a5-fluoro-2-methoxypyrimidin-4-yl group, a 2,5-dimethylpyrimidin-4-ylgroup or a 2-methylpyrimidin-4-yl group], the manufacturing methodincluding a stage in which a compound represented by formula (AD-2) isobtained [this stage is the same as (stage [3a]-1) in mode [3a] above;and the definitions of the substituent groups in the intermediate in(stage [3a]-1) are the same as the definitions in mode [3a-3]].

[4] A fourth mode of the present invention is a method for manufacturinga compound represented by formula (I) below:

[in formula (I), p denotes an integer between 0 and 3; q denotes aninteger between 0 and 2; R¹ groups each independently denote a grouparbitrarily selected from among a halogen atom, a cyano group, a C₁₋₆alkyl group, a halogenated C₁₋₆ alkyl group and a C₁₋₆ alkoxy group; R²denotes a C₁₋₆ alkyl group; R³ denotes a group arbitrarily selected fromamong a hydrogen atom and a fluorine atom; R⁴ groups each independentlydenote a group arbitrarily selected from among a halogen atom, a C₁₋₆alkyl group and a C₁₋₆ alkoxy group; and ring A group represented byformula (II):

denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarilyselected from among a pyridin-2-yl group, a pyridazin-3-yl group, apyrimidin-2-yl group, a pyrimidin-4-yl group and a pyrazin-2-yl group],the manufacturing method including stages in which a compoundrepresented by formula (AD-2):

[in formula (AD-2), p, R¹, R², R³ and ring A group represented byformula (II) are defined in the same way as for formula (I) in mode [4]]and a compound represented by formula (IM-1):

[in formula (IM-1), q and R⁴ are defined in the same way as for formula(I) in mode [4]; and R^(B) denotes a C₁₋₆ alkyl group] or a salt thereof(the compound represented by formula (IM-1) and salt thereof arecommercially available compounds or compounds that can be easilyobtained from commercially available compounds using manufacturingmethods known from literature) are reacted with each other using asolvent which does not take part in the reaction, such as dimethylsulfoxide or pyridine, at a temperature between 0° C. and a temperatureat which the solvent refluxes thereby obtaining a compound representedby formula (AD-3):

[in formula (AD-3), p, q, R¹, R², R³, R⁴ and ring A group represented byformula (II) are defined in the same way as for formula (I) in mode [4]](stage [4]-1), and the compound represented by formula (AD-3) issubjected to a cyclization reaction in the presence of air using asolvent which does not take part in the reaction, such as dimethylsulfoxide (DMSO) or N-methylpyrrolidone (NMP), at a temperature between0° C. and a temperature at which the solvent refluxes in the presence ofa copper reagent such as copper iodide (CuI) or copper chloride (CuCl)(stage [4]-2), thereby obtaining the compound represented by formula(I).

[4-1] A preferred aspect of mode [4] is a method in which a compoundrepresented by formula (I) above is manufactured [in formula (I), p, q,R³ and ring A group represented by formula (II) are defined in the sameway as for mode [4] above; R¹ denotes a group arbitrarily selected fromamong a fluorine atom, a chlorine atom, a cyano group, a methyl group, atrifluoromethyl group and a methoxy group; R² denotes a methyl group;and R⁴ denotes a group arbitrarily selected from among a fluorine atom,a methyl group and a methoxy group], the manufacturing method includingstages in which a compound represented by formula (I) is obtained [thesestages are the same as (stage [4]-1) and (stage [4]-2) in mode [4]above; the definitions of the substituent groups in the intermediates in(stage [4]-1) and (stage [4]-2) are the same as the definitions in mode[4-1], and R^(B) in formula (IM-1) is a C₁₋₆ alkyl group].

[4-2] A more preferred aspect of mode [4] is a method in which acompound represented by formula (I) above is manufactured [in formula(I), p, R¹, R², R⁴ and ring A group represented by formula (II) aredefined in the same way as for mode [4-1] above; q denotes the integer0; and R³ denotes a fluorine atom], the manufacturing method includingstages in which a compound represented by formula (I) is obtained [thesestages are the same as (stage [4]-1) and (stage [4]-2) in mode [4]above; the definitions of the substituent groups in the intermediates in(stage [4]-1) and (stage [4]-2) are the same as the definitions in mode[4-2], and R^(B) in formula (IM-1) is a C₁₋₆ alkyl group].

[4-3] A yet more preferred aspect of mode [4] is a method in which acompound represented by formula (I) above is manufactured [in formula(I), p, q, R¹, R², R³ and R⁴ are defined in the same way as for mode[4-2] above; ring A group represented by formula (II) is apyrimidin-4-yl group; and a more specific group obtained by combiningthe definitions of p, R¹ and ring A group represented by formula (II) isa 2,5-dimethylpyrimidin-4-yl group], the manufacturing method includingstages in which a compound represented by formula (I) is obtained [thesestages are the same as (stage [4]-1) and (stage [4]-2) in mode [4]above; the definitions of the substituent groups in the intermediates in(stage [4]-1) and (stage [4]-2) are the same as the definitions in mode[4-3], and R^(B) in formula (IM-1) is a C₁₋₆ alkyl group].

[4a] Another aspect of the fourth mode of the present invention is amethod for manufacturing a compound represented by formula (I) below:

[in formula (I), p denotes an integer between 0 and 3; q denotes aninteger between 0 and 2; R¹ groups each independently denote a grouparbitrarily selected from among a halogen atom, a cyano group, a C₁₋₆alkyl group, a C₃₋₈ cycloalkyl group, a halogenated C₁₋₆ alkyl group, aC₂₋₆ alkenyl group, a C₁₋₆ alkoxy group, a C₁₋₆ alkoxy-C₁₋₆ alkyl group,a hydroxy-C₁₋₆ alkyl group and a C₂₋₇ alkanoyl group; R² denotes a C₁₋₆alkyl group; R³ denotes a group arbitrarily selected from among ahydrogen atom and a fluorine atom; R⁴ groups each independently denote agroup arbitrarily selected from among a halogen atom, a C₁₋₆ alkyl groupand a C₁₋₆ alkoxy group; and ring A group represented by formula (II):

denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarilyselected from among a thiazol-2-yl group, a thiazol-4-yl group, a1-methyl-1H-imidazol-4-yl group, a 1,3,4-thiadiazol-2-yl group, a1,2,4-thiadiazol-5-yl group, a pyridin-2-yl group, a pyridazin-3-ylgroup, a pyrimidin-2-yl group, a pyrimidin-4-yl group and a pyrazin-2-ylgroup], the manufacturing method including stages in which a compoundrepresented by formula (AD-2):

[in formula (AD-2), p, R¹, R², R³ and ring A group represented byformula (II) are defined in the same way as for formula (I) in mode[4a]] and a compound represented by formula (IM-1):

[in formula (IM-1), q and R⁴ are defined in the same way as for formula(I) in mode [4a]; and R^(B) denotes a C₁₋₆ alkyl group] or a saltthereof (the compound represented by formula (IM-1) and salt thereof arecommercially available compounds or compounds that can be easilyobtained from commercially available compounds using manufacturingmethods known from literature) are reacted with each other using asolvent which does not take part in the reaction, such as dimethylsulfoxide or pyridine, at a temperature between 0° C. and a temperatureat which the solvent refluxes, thereby obtaining a compound representedby formula (AD-3):

[in formula (AD-3), p, q, R¹, R², R³, R⁴ and ring A group represented byformula (II) are defined in the same way as for formula (I) in mode[4a]] (stage [4a]-1), and the compound represented by formula (AD-3) issubjected to a cyclization reaction in the presence of air using asolvent which does not take part in the reaction, such as dimethylsulfoxide (DMSO) or N-methylpyrrolidone (NMP), at a temperature between0° C. and a temperature at which the solvent refluxes in the presence ofa copper reagent such as copper iodide (CuI) or copper chloride (CuCl)(stage [4a]-2), thereby obtaining the compound represented by formula(I).

[4a-1] A preferred aspect of mode [4a] is a method in which a compoundrepresented by formula (I) above is manufactured [in formula (I), p, q,R³ and ring A group represented by formula (II) are defined in the sameway as in mode [4a] above; R¹ denotes a group arbitrarily selected fromamong a fluorine atom, a chlorine atom, a bromine atom, a cyano group, amethyl group, an ethyl group, an isopropyl group, a tert-butyl group, acyclopropyl group, a difluoromethyl group, a trifluoromethyl group, a1-hydroxyethyl group, a vinyl group, an acetyl group, a methoxy groupand an ethoxyethyl group; R² denotes a methyl group; and R⁴ denotes agroup arbitrarily selected from among a fluorine atom, a methyl groupand a methoxy group], the manufacturing method including stages in whicha compound represented by formula (I) is obtained [these stages are thesame as (stage [4a]-1) and (stage [4a]-2) in mode [4a] above; thedefinitions of the substituent groups in the intermediates in (stage[4a]-1) and (stage [4a]-2) are the same as the definitions in mode[4a-1], and R^(B) in formula (IM-1) is a C₁₋₆ alkyl group].

[4a-2] A more preferred aspect of mode [4a] is a method in which acompound represented by formula (I) above is manufactured [in formula(I), p, R¹, R², R⁴ and ring A group represented by formula (II) aredefined in the same way as for mode [4a-1] above; q denotes the integer0; and R³ denotes a fluorine atom], the manufacturing method includingstages in which a compound represented by formula (I) is obtained [thesestages are the same as (stage [4a]-1) and (stage [4a]-2) in mode [4a]above; the definitions of the substituent groups in the intermediates in(stage [4a]-1) and (stage [4a]-2) are the same as the definitions inmode [4a-2], and R^(B) in formula (IM-1) is a C₁₋₆ alkyl group].

[4a-3] A yet more preferred aspect of mode [4a] is a method in which acompound represented by formula (I) above is manufactured [in formula(I), p, q, R¹, R², R³ and R⁴ are defined in the same way as for mode[4a-2] above; ring A group represented by formula (II) is a thiazol-2-ylgroup or a pyrimidin-4-yl group; and a more specific group obtained bycombining the definitions of p, R¹ and ring A group represented byformula (II) is a 4-(trifluoromethyl)thiazol-2-yl group, a5-fluoro-2-methoxypyrimidin-4-yl group, a 2,5-dimethylpyrimidin-4-ylgroup or a 2-methylpyrimidin-4-yl group], the manufacturing methodincluding stages in which a compound represented by formula (I) isobtained [these stages are the same as (stage [4a]-1) and (stage [4a]-2)in mode [4a] above; the definitions of the substituent groups in theintermediates in (stage [4a]-1) and (stage [4a]-2) are the same as thedefinitions in mode [4a-3], and R^(B) in formula (IM-1) is a C₁₋₆ alkylgroup].

[5] A fifth mode of the present invention is a method for manufacturinga compound represented by formula (I) below:

[in formula (I), p denotes an integer between 0 and 3; q denotes aninteger between 0 and 2; R¹ groups each independently denote a grouparbitrarily selected from among a halogen atom, a cyano group, a C₁₋₆alkyl group, a halogenated C₁₋₆ alkyl group and a C₁₋₆ alkoxy group; R²denotes a C₁₋₆ alkyl group; R³ denotes a group arbitrarily selected fromamong a hydrogen atom and a fluorine atom; R⁴ groups each independentlydenote a group arbitrarily selected from among a halogen atom, a C₁₋₆alkyl group and a C₁₋₆ alkoxy group; and ring A group represented byformula (II):

denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarilyselected from among a pyridin-2-yl group, a pyridazin-3-yl group, apyrimidin-2-yl group, a pyrimidin-4-yl group and a pyrazin-2-yl group],the manufacturing method including a stage in which a compoundrepresented by formula (AD-3):

[in formula (AD-3), p, q, R¹, R², R³, R⁴ and ring A group represented byformula (II) are defined in the same way as for formula (I) in mode [5]]is subjected to a cyclization reaction in the presence of air using asolvent which does not take part in the reaction, such as dimethylsulfoxide (DMSO) or N-methylpyrrolidone (NMP), at a temperature between0° C. and a temperature at which the solvent refluxes in the presence ofa copper reagent such as copper iodide (CuI) or copper chloride (CuCl)(stage [5]-1), thereby obtaining the compound represented by formula(I).

[5-1] A preferred aspect of mode [5] is a method in which a compoundrepresented by formula (I) above is manufactured [in formula (I), p, q,R³ and ring A group represented by formula (II) are defined in the sameway as for mode [5] above; R¹ denotes a group arbitrarily selected fromamong a fluorine atom, a chlorine atom, a cyano group, a methyl group, atrifluoromethyl group and a methoxy group; R² denotes a methyl group;and R⁴ denotes a group arbitrarily selected from among a fluorine atom,a methyl group and a methoxy group], the manufacturing method includinga stage in which a compound represented by formula (I) is obtained [thisstage is the same as (stage [5]-1) in mode [5] above; and thedefinitions of the substituent groups in the intermediate in (stage[5]-1) are the same as the definitions in mode [5-1]].

[5-2] A more preferred aspect of mode [5] is a method in which acompound represented by formula (I) above is manufactured [in formula(I), p, R¹, R², R⁴ and ring A group represented by formula (II) aredefined in the same way as for mode [5-1] above; q denotes the integer0; and R³ denotes a fluorine atom], the manufacturing method including astage in which a compound represented by formula (I) is obtained [thisstage is the same as (stage [5]-1) in mode [5] above; and thedefinitions of the substituent groups in the intermediate in (stage[5]-1) are the same as the definitions in mode [5-2]].

[5-3] A yet more preferred aspect of mode [5] is a method in which acompound represented by formula (I) above is manufactured [in formula(I), p, q, R¹, R², R³ and R⁴ are defined in the same way as for mode[5-2] above; ring A group represented by formula (II) is apyrimidin-4-yl group; and a more specific group obtained by combiningthe definitions of p, R¹ and ring A group represented by formula (II) isa 2,5-dimethylpyrimidin-4-yl group], the manufacturing method includinga stage in which a compound represented by formula (I) is obtained [thisstage is the same as (stage [5]-1) in mode [5] above; and thedefinitions of the substituent groups in the intermediate in (stage[5]-1) are the same as the definitions in mode [5-3]].

[5a] Another aspect of the fifth mode of the present invention is amethod for manufacturing a compound represented by formula (I) below:

[in formula (I), p denotes an integer between 0 and 3; q denotes aninteger between 0 and 2; R¹ groups each independently denote a grouparbitrarily selected from among a halogen atom, a cyano group, a C₁₋₆alkyl group, a C₃₋₈ cycloalkyl group, a halogenated C₁₋₆ alkyl group, aC₂₋₆ alkenyl group, a C₁₋₆ alkoxy group, a C₁₋₆ alkoxy-C₁₋₆ alkyl group,a hydroxy-C₁₋₆ alkyl group and a C₂₋₇ alkanoyl group; R² denotes a C₁₋₆alkyl group; R³ denotes a group arbitrarily selected from among ahydrogen atom and a fluorine atom; R⁴ groups each independently denote agroup arbitrarily selected from among a halogen atom, a C₁₋₆ alkyl groupand a C₁₋₆ alkoxy group; and ring A group represented by formula (II):

denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarilyselected from among a thiazol-2-yl group, a thiazol-4-yl group, a1-methyl-1H-imidazol-4-yl group, a 1,3,4-thiadiazol-2-yl group, a1,2,4-thiadiazol-5-yl group, a pyridin-2-yl group, a pyridazin-3-ylgroup, a pyrimidin-2-yl group, a pyrimidin-4-yl group and a pyrazin-2-ylgroup], the manufacturing method including a stage in which a compoundrepresented by formula (AD-3):

[in formula (AD-3), p, q, R¹, R², R³, R⁴ and ring A group represented byformula (II) are defined in the same way as for formula (I) in mode[5a]] is subjected to a cyclization reaction in the presence of airusing a solvent which does not take part in the reaction, such asdimethyl sulfoxide (DMSO) or N-methylpyrrolidone (NMP), at a temperaturebetween 0° C. and a temperature at which the solvent refluxes in thepresence of a copper reagent such as copper iodide (CuI) or copperchloride (CuCl) (stage [5a]-1), thereby obtaining the compoundrepresented by formula (I).

[5a-1] A preferred aspect of mode [5a] is a method in which a compoundrepresented by formula (I) above is manufactured [in formula (I), p, q,R³ and ring A group represented by formula (II) are defined in the sameway as in mode [5a] above; R¹ denotes a group arbitrarily selected fromamong a fluorine atom, a chlorine atom, a bromine atom, a cyano group, amethyl group, an ethyl group, an isopropyl group, a tert-butyl group, acyclopropyl group, a difluoromethyl group, a trifluoromethyl group, a1-hydroxyethyl group, a vinyl group, an acetyl group, a methoxy groupand an ethoxyethyl group; R² denotes a methyl group; and R⁴ denotes agroup arbitrarily selected from among a fluorine atom, a methyl groupand a methoxy group], the manufacturing method including a stage inwhich a compound represented by formula (I) is obtained [this stage isthe same as (stage [5a]-1) in mode [5a] above; and the definitions ofthe substituent groups in the intermediate in (stage [5a]-1) are thesame as the definitions in mode [5a-1]].

[5a-2] A more preferred aspect of mode [5a] is a method in which acompound represented by formula (I) above is manufactured [in formula(I), p, R¹, R², R⁴ and ring A group represented by formula (II) aredefined in the same way as for mode [5a-1] above; q denotes the integer0; and R³ denotes a fluorine atom], the manufacturing method including astage in which a compound represented by formula (I) is obtained [thisstage is the same as (stage [5a]-1) in mode [5a] above; and thedefinitions of the substituent groups in the intermediate in (stage[5a]-1) are the same as the definitions in mode [5a-2]].

[5a-3] A yet more preferred aspect of mode [5a] is a method in which acompound represented by formula (I) above is manufactured [in formula(I), p, q, R¹, R², R³ and R⁴ are defined in the same way as for mode[5a-2] above; ring A group represented by formula (II) is a thiazol-2-ylgroup or a pyrimidin-4-yl group; and a more specific group obtained bycombining the definitions of p, R¹ and ring A group represented byformula (II) is a 4-(trifluoromethyl)thiazol-2-yl group, a5-fluoro-2-methoxypyrimidin-4-yl group, a 2,5-dimethylpyrimidin-4-ylgroup or a 2-methylpyrimidin-4-yl group], the manufacturing methodincluding a stage in which a compound represented by formula (I) isobtained [this stage is the same as (stage [5a]-1) in mode [5a] above;and the definitions of the substituent groups in the intermediate in(stage [5a]-1) are the same as the definitions in mode [5a-3]].

[6] A sixth mode of the present invention is a method for manufacturinga compound represented by formula (I) below:

[in formula (I), p denotes an integer between 0 and 3; q denotes aninteger between 0 and 2; R¹ groups each independently denote a grouparbitrarily selected from among a halogen atom, a cyano group, a C₁₋₆alkyl group, a halogenated C₁₋₆ alkyl group and a C₁₋₆ alkoxy group; R²denotes a C₁₋₆ alkyl group; R³ denotes a group arbitrarily selected fromamong a hydrogen atom and a fluorine atom; R⁴ groups each independentlydenote a group arbitrarily selected from among a halogen atom, a C₁₋₆alkyl group and a C₁₋₆ alkoxy group; and ring A group represented byformula (II):

denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarilyselected from among a pyridin-2-yl group, a pyridazin-3-yl group, apyrimidin-2-yl group, a pyrimidin-4-yl group and a pyrazin-2-yl group],the manufacturing method including stages in which a compoundrepresented by formula (ET-1):

[in formula (ET-1), p, R¹ and R² are defined in the same way as forformula (I) in mode [6]; R^(D) denotes a group arbitrarily selected fromamong a C₁₋₆ alkyl group, a C₆₋₁₄ aryl group and a C₇₋₂₀ aralkyl group(a routine method for manufacturing a compound represented by formula(ET-1) is described later)] is subjected to hydrolysis [in cases whereR^(D) is a C₁₋₆ alkyl group (for example, a methyl group, an ethylgroup, or the like), a C₆₋₁₄ aryl group (for example, a phenyl group orthe like) or a C₇₋₂₀ aralkyl group (for example, a benzyl group), areaction is carried out in the presence of a base such as lithiumhydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate,sodium carbonate or potassium carbonate using a solvent that is inert inthe reaction, such as water, methanol, ethanol, 2-propanol,N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran or a mixture thereofat a temperature between 0° C. and a temperature at which the solventrefluxes; in cases where R^(D) is a tert-butyl group (a C₁₋₆ alkylgroup), a reaction with an acid such as hydrochloric acid ortrifluoroacetic acid is carried out] or hydrogenation [in cases whereR^(D) is a C₇₋₂₀ aralkyl group (for example, a benzyl group or thelike), a reaction is carried out in the presence of a catalyst such aspalladium-carbon (Pd—C), Raney-nickel (Raney-Ni) or platinum oxide(PtO₂) in a hydrogen gas atmosphere using a solvent which does not takepart in the reaction, such as an alcoholic solvent such as methanol,ethanol or 2-propanol, an ether-based solvent such as diethyl ether,tetrahydrofuran, 1,2-dimethoxyethane or 1,4-dioxane, or a polar solventsuch as ethyl acetate or methyl acetate, or a mixture thereof, at atemperature between 0° C. and a temperature at which the solventrefluxes], thereby obtaining a compound represented by formula (CA-1):

[in formula (CA-1), p, R¹ and R² are defined in the same way as forformula (I) in mode [6]] (stage [6]-1), the compound represented byformula (CA-1) and a compound represented by formula (PY-2):

[in formula (PY-2), R³ denotes a group arbitrarily selected from among ahydrogen atom and a fluorine atom; R^(C) denotes a group arbitrarilyselected from among a C₁₋₆ alkyl group, a C₆₋₁₄ aryl group and a C₇₋₂₀aralkyl group (a routine method for manufacturing a compound representedby formula (PY-2) is described later)] are reacted with each other inthe presence of a condensing agent such as 1,3-dicyclohexylcarbodiimide(DCC), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride(WSC.HCl), 1-hydroxybenzotriazole (Hobt),benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate(a BOP reagent), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl),2-chloro-1,3-dimethylimidazolinium hexafluorophosphate (CIP),4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride(DMTMM), polyphosphoric acid (PPA) or2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate methanaminium (HATU), in the presence or absence ofa base such as N,N-diisopropylethylamine, triethylamine, pyridine orlutidine, in a solvent which does not take part in the reaction, such asdichloromethane, chloroform, diethyl ether, tetrahydrofuran, toluene,benzene, N,N-dimethylformamide, N-methylpyrrolidone, methanol, ethanolor 2-propanol at a temperature between 0° C. and a temperature at whichthe solvent refluxes, thereby obtaining a compound represented byformula (AD-4):

[in formula (AD-4), p, R¹, R² and R³ are defined in the same way as forformula (I) in mode [6]; and R^(C) denotes a group arbitrarily selectedfrom among a C₁₋₆ alkyl group, a C₆₋₁₄ aryl group and a C₇₋₂₀ aralkylgroup] (stage [6]-2), a —C(═O)OR^(C) group (R^(C) denotes a grouparbitrarily selected from among a C₁₋₆ alkyl group, a C₆₋₁₄ aryl groupand a C₇₋₂₀ aralkyl group), which is a protecting group for an aminogroup in formula (AD-4) is deprotected using a method known fromliterature, for example, a method disclosed in Greene et al.,“Protective Groups in Organic Synthesis”, fourth edition, 2007 (JohnWiley & Sons), or using articles that have been publicly expressed,thereby obtaining a compound represented by formula (AD-2):

[in formula (AD-2), p, R¹, R² and R³ are defined in the same way as forformula (I) in mode [6]] (stage [6]-3), the compound represented byformula (AD-2) and a compound represented by formula (IM-1):

[in formula (IM-1), q and R⁴ are defined in the same way as for formula(I) in mode [6]; and R^(B) denotes a C₁₋₆ alkyl group] or a salt thereof(the compound represented by formula (IM-1) and salt thereof arecommercially available compounds or compounds that can be easilyobtained from commercially available compounds using manufacturingmethods known from literature) are reacted with each other using asolvent which does not take part in the reaction, such as dimethylsulfoxide or pyridine, at a temperature between 0° C. and a temperatureat which the solvent refluxes, thereby obtaining a compound representedby formula (AD-3):

[in formula (AD-3), p, q, R¹, R², R³, R⁴ and ring A group represented byformula (II) are defined in the same way as for formula (I) in mode [6]](stage [6]-4), and the compound represented by formula (AD-3) issubjected to a cyclization reaction in the presence of air using asolvent which does not take part in the reaction, such as dimethylsulfoxide (DMSO) or N-methylpyrrolidone (NMP), at a temperature between0° C. and a temperature at which the solvent refluxes in the presence ofa copper reagent such as copper iodide (CuI) or copper chloride (CuCl)(stage [6]-5), thereby obtaining the compound represented by formula(I).

[6-1] A preferred aspect of mode [6] is a method in which a compoundrepresented by formula (I) above is manufactured [in formula (I), p, q,R³ and ring A group represented by formula (II) are defined in the sameway as for mode [6] above; R¹ denotes a group arbitrarily selected fromamong a fluorine atom, a chlorine atom, a cyano group, a methyl group, atrifluoromethyl group and a methoxy group; R² denotes a methyl group;and R⁴ denotes a group arbitrarily selected from among a fluorine atom,a methyl group and a methoxy group], the manufacturing method includingstages in which a compound represented by formula (I) is obtained [thesestages are the same as (stage [6]-1) to (stage [6]-5) in mode [6] above;and the definitions of the substituent groups in the intermediates in(stage [6]-1) to (stage [6]-5) are the same as the definitions in mode[6-1]].

[6-2] A more preferred aspect of mode [6] is a method in which acompound represented by formula (I) above is manufactured [in formula(I), p, R¹, R², R⁴ and ring A group represented by formula (II) aredefined in the same way as for mode [6-1] above; q denotes the integer0; and R³ denotes a fluorine atom], the manufacturing method includingstages in which a compound represented by formula (I) is obtained [thesestages are the same as (stage [6]-1) to (stage [6]-5) in mode [6]above;and the definitions of the substituent groups in the intermediates in(stage [6]-1) to (stage [6]-5) are the same as the definitions in mode[6-2]].

[6-3] A yet more preferred aspect of mode [6] is a method in which acompound represented by formula (I) above is manufactured [in formula(I), p, q, R¹, R², R³ and R⁴ are defined in the same way as for mode[6-2] above; ring A group represented by formula (II) is apyrimidin-4-yl group; and a more specific group obtained by combiningthe definitions of p, R¹ and ring A group represented by formula (II) isa 2,5-dimethylpyrimidin-4-yl group], the manufacturing method includingstages in which a compound represented by formula (I) is obtained [thesestages are the same as (stage [6]-1) to (stage [6]-5) in mode [6] above;and the definitions of the substituent groups in the intermediates in(stage [6]-1) to (stage [6]-5) are the same as the definitions in mode[6-3]].

[6a] Another aspect of the sixth mode of the present invention is amethod for manufacturing a compound represented by formula (I) below:

[in formula (I), p denotes an integer between 0 and 3; q denotes aninteger between 0 and 2; R¹ groups each independently denote a grouparbitrarily selected from among a halogen atom, a cyano group, a C₁₋₆alkyl group, a C₃₋₈ cycloalkyl group, a halogenated C₁₋₆ alkyl group, aC₂₋₆ alkenyl group, a C₁₋₆ alkoxy group, a C₁₋₆ alkoxy-C₁₋₆ alkyl group,a hydroxy-C₁₋₆ alkyl group and a C₂₋₇ alkanoyl group; R² denotes a C₁₋₆alkyl group; R³ denotes a group arbitrarily selected from among ahydrogen atom and a fluorine atom; R⁴ groups each independently denote agroup arbitrarily selected from among a halogen atom, a C₁₋₆ alkyl groupand a C₁₋₆ alkoxy group; and ring A group represented by formula (II):

denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarilyselected from among a thiazol-2-yl group, a thiazol-4-yl group, a1-methyl-1H-imidazol-4-yl group, a 1,3,4-thiadiazol-2-yl group, a1,2,4-thiadiazol-5-yl group, a pyridin-2-yl group, a pyridazin-3-ylgroup, a pyrimidin-2-yl group, a pyrimidin-4-yl group and a pyrazin-2-ylgroup], the manufacturing method including stages in which a compoundrepresented by formula (ET-1):

[in formula (ET-1), p, R¹ and R² are defined in the same way as forformula (I) in mode [6a]; R^(D) denotes a group arbitrarily selectedfrom among a C₁₋₆ alkyl group, a C₆₋₁₄ aryl group and a C₇₋₂₀ aralkylgroup (a routine method for manufacturing a compound represented byformula (ET-1) is described later)] is subjected to hydrolysis [in caseswhere R^(D) is a C₁₋₆ alkyl group (for example, a methyl group, an ethylgroup, or the like), a C₆₋₁₄ aryl group (for example, a phenyl group orthe like) or a C₇₋₂₀ aralkyl group (for example, a benzyl group), areaction is carried out in the presence of a base such as lithiumhydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate,sodium carbonate or potassium carbonate using a solvent that is inert inthe reaction, such as water, methanol, ethanol, 2-propanol,N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran or a mixture thereofat a temperature between 0° C. and a temperature at which the solventrefluxes; in cases where R^(D) is a tert-butyl group (a C₁₋₆ alkylgroup), a reaction with an acid such as hydrochloric acid ortrifluoroacetic acid is carried out] or hydrogenation [in cases whereR^(D) is a C₇₋₂₀ aralkyl group (for example, a benzyl group or thelike), a reaction is carried out in the presence of a catalyst such aspalladium-carbon (Pd—C), Raney-nickel (Raney-Ni) or platinum oxide(PtO₂) in a hydrogen gas atmosphere using a solvent which does not takepart in the reaction, such as an alcoholic solvent such as methanol,ethanol or 2-propanol, an ether-based solvent such as diethyl ether,tetrahydrofuran, 1,2-dimethoxyethane or 1,4-dioxane, or a polar solventsuch as ethyl acetate or methyl acetate, or a mixture thereof, at atemperature between 0° C. and a temperature at which the solventrefluxes], thereby obtaining a compound represented by formula (CA-1):

[in formula (CA-1), p, R¹ and R² are defined in the same way as forformula (I) in mode [6a]] (stage [6a]-1), the compound represented byformula (CA-1) and a compound represented by formula (PY-2):

[in formula (PY-2), R³ denotes a group arbitrarily selected from among ahydrogen atom and a fluorine atom; R^(C) denotes a group arbitrarilyselected from among a C₁₋₆ alkyl group, a C₆₋₁₄ aryl group and a C₇₋₂₀aralkyl group (a routine method for manufacturing a compound representedby formula (PY-2) is described later)] are reacted with each other inthe presence of a condensing agent such as 1,3-dicyclohexylcarbodiimide(DCC), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride(WSC.HCl), 1-hydroxybenzotriazole (Hobt),benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate(a BOP reagent), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl),2-chloro-1,3-dimethylimidazolinium hexafluorophosphate (CIP),4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride(DMTMM), polyphosphoric acid (PPA) or2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate methanaminium (HATU), in the presence or absence ofa base such as N,N-diisopropylethylamine, triethylamine, pyridine orlutidine, in a solvent which does not take part in the reaction, such asdichloromethane, chloroform, diethyl ether, tetrahydrofuran, toluene,benzene, N,N-dimethylformamide, N-methylpyrrolidone, methanol, ethanolor 2-propanol at a temperature between 0° C. and a temperature at whichthe solvent refluxes, thereby obtaining a compound represented byformula (AD-4):

[in formula (AD-4), p, R¹, R² and R³ are defined in the same way as forformula (I) in mode [6a]; and R^(C) denotes a group arbitrarily selectedfrom among a C₁₋₆ alkyl group, a C₆₋₁₄ aryl group and a C₇₋₂₀ aralkylgroup] (stage [6a]-2), a —C(═O)OR^(C) group (R^(C) denotes a grouparbitrarily selected from among a C₁₋₆ alkyl group, a C₆₋₁₄ aryl groupand a C₇₋₂₀ aralkyl group), which is a protecting group for an aminogroup in formula (AD-4) is deprotected using a method known fromliterature, for example, a method disclosed in Greene et al.,“Protective Groups in Organic Synthesis”, fourth edition, 2007 (JohnWiley & Sons), or using articles that have been publicly expressed,thereby obtaining a compound represented by formula (AD-2):

[in formula (AD-2), p, R¹, R² and R³ are defined in the same way as forformula (I) in mode [6a]] (stage [6a]-3), the compound represented byformula (AD-2) and a compound represented by formula (IM-1):

[in formula (IM-1), q and R⁴ are defined in the same way as for formula(I) in mode [6a]; and R^(B) denotes a C₁₋₆alkyl group] or a salt thereof(the compound represented by formula (IM-1) and salt thereof arecommercially available compounds or compounds that can be easilyobtained from commercially available compounds using manufacturingmethods known from literature) are reacted with each other using asolvent which does not take part in the reaction, such as dimethylsulfoxide or pyridine, at a temperature between 0° C. and a temperatureat which the solvent refluxes, thereby obtaining a compound representedby formula (AD-3):

[in formula (AD-3), p, q, R¹, R², R³, R⁴ and ring A group represented byformula (II) are defined in the same way as for formula (I) in mode[6a]] (stage [6a]-4), and the compound represented by formula (AD-3) issubjected to a cyclization reaction in the presence of air using asolvent which does not take part in the reaction, such as dimethylsulfoxide (DMSO) or N-methylpyrrolidone (NMP), at a temperature between0° C. and a temperature at which the solvent refluxes in the presence ofa copper reagent such as copper iodide (CuI) or copper chloride (CuCl)(stage [6a]-5), thereby obtaining the compound represented by formula(I).

[6a-1] A preferred aspect of mode [6a] is a method in which a compoundrepresented by formula (I) above is manufactured [in formula (I), p, q,R³ and ring A group represented by formula (II) are defined in the sameway as in mode [6a] above; R¹ denotes a group arbitrarily selected fromamong a fluorine atom, a chlorine atom, a bromine atom, a cyano group, amethyl group, an ethyl group, an isopropyl group, a tert-butyl group, acyclopropyl group, a difluoromethyl group, a trifluoromethyl group, a1-hydroxyethyl group, a vinyl group, an acetyl group, a methoxy groupand an ethoxyethyl group; R² denotes a methyl group; and R⁴ denotes agroup arbitrarily selected from among a fluorine atom, a methyl groupand a methoxy group], the manufacturing method including stages in whicha compound represented by formula (I) is obtained [these stages are thesame as (stage [6a]-1) to (stage [6a]-5) in mode [6a] above; and thedefinitions of the substituent groups in the intermediates in (stage[6a]-1) to (stage [6a]-5) are the same as the definitions in mode[6a-1]].

[6a-2] A more preferred aspect of mode [6a] is a method in which acompound represented by formula (I) above is manufactured [in formula(I), p, R¹, R², R⁴ and ring A group represented by formula (II) aredefined in the same way as for mode [6a-1] above; q denotes the integer0; and R³ denotes a fluorine atom], the manufacturing method includingstages in which a compound represented by formula (I) is obtained [thesestages are the same as (stage [6a]-1) to (stage [6a]-5) in mode [6a]above; and the definitions of the substituent groups in theintermediates in (stage [6a]-1) to (stage [6a]-5) are the same as thedefinitions in mode [6a-2]].

[6a-3] A yet more preferred aspect of mode [6a] is a method in which acompound represented by formula (I) above is manufactured [in formula(I), p, q, R¹, R², R³ and R⁴ are defined in the same way as for mode[6a-2] above; ring A group represented by formula (II) is a thiazol-2-ylgroup or a pyrimidin-4-yl group; and a more specific group obtained bycombining the definitions of p, R¹ and ring A group represented byformula (II) is a 4-(trifluoromethyl)thiazol-2-yl group, a5-fluoro-2-methoxypyrimidin-4-yl group, a 2,5-dimethylpyrimidin-4-ylgroup or a 2-methylpyrimidin-4-yl group], the manufacturing methodincluding stages in which a compound represented by formula (I) isobtained [these stages are the same as (stage [6a]-1) to (stage [6a]-5)in mode [6a] above; and the definitions of the substituent groups in theintermediates in (stage [6a]-1) to (stage [6a]-5) are the same as thedefinitions in mode [6a-3]].

[7] A seventh mode of the present invention is a method formanufacturing a compound represented by formula (AD-2) below:

[in formula (AD-2), p denotes an integer between 0 and 3; R¹ groups eachindependently denote a group arbitrarily selected from among a halogenatom, a cyano group, a C₁₋₆ alkyl group, a halogenated C₁₋₆ alkyl groupand a C₁₋₆ alkoxy group; R² denotes a C₁₋₆ alkyl group; R³ denotes agroup arbitrarily selected from among a hydrogen atom and a fluorineatom; and ring A group represented by formula (II):

denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarilyselected from among a pyridin-2-yl group, a pyridazin-3-yl group, apyrimidin-2-yl group, a pyrimidin-4-yl group and a pyrazin-2-yl group],the manufacturing method including stages in which a compoundrepresented by formula (ET-1):

[in formula (ET-1), p, R¹, R² and ring A group represented by formula(II) are defined in the same way as for formula (AD-2) in mode [7];R^(D) denotes a group arbitrarily selected from among a C₁₋₆ alkylgroup, a C₆14 aryl group and a C₇₋₂₀ aralkyl group (a routine method formanufacturing a compound represented by formula (ET-1) is describedlater)] is subjected to hydrolysis or hydrogenation (these are the sameas the reactions described in mode [6] above) according to the type ofR^(D)group, thereby obtaining a compound represented by formula (CA-1):

[in formula (CA-1), p, R¹, R² and ring A group represented by formula(II) are defined in the same way as for formula (I) in mode [7]] (stage[7]-1), the compound represented by formula (CA-1) and a compoundrepresented by formula (PY-2):

[in formula (PY-2), R³ denotes a group arbitrarily selected from among ahydrogen atom and a fluorine atom; R^(C) denotes a group arbitrarilyselected from among a C₁₋₆ alkyl group, a C₆₋₁₄ aryl group and a C₇₋₂₀aralkyl group (a routine method for manufacturing a compound representedby formula (PY-2) is described later)] are reacted with each other inthe presence of a condensing agent (condensing agents are the same asthe condensing agents described in mode [6] above), in the presence orabsence of a base such as N,N-diisopropylethylamine, triethylamine,pyridine or lutidine, in a solvent which does not take part in thereaction, such as dichloromethane, chloroform, diethyl ether,tetrahydrofuran, toluene, benzene, N,N-dimethylformamide,N-methylpyrrolidone, methanol, ethanol or 2-propanol at a temperaturebetween 0° C. and a temperature at which the solvent refluxes, therebyobtaining a compound represented by formula (AD-4):

[in formula (AD-4), p, R¹, R², R³ and ring A group represented byformula (II) are defined in the same way as for formula (AD-2) in mode[7]; and R^(C) denotes a group arbitrarily selected from among a C₁₋₆alkyl group, a C₆₋₁₄ aryl group and a C₇₋₂₀ aralkyl group] (stage[7]-2), and a —C(═O)OR^(C) group (R^(C) denotes a group arbitrarilyselected from among a C₁₋₆ alkyl group, a C₆₋₁₄ aryl group and a C₇₋₂₀aralkyl group), which is a protecting group for an amino group informula (AD-4) is deprotected (according to the deprotection methoddescribed in mode [6] above) (stage [7]-3), thereby obtaining thecompound represented by formula (AD-2).

[7-1] A preferred aspect of mode [7] is a method in which a compoundrepresented by formula (AD-2) above is manufactured [in formula (AD-2),p, R³ and ring A group represented by formula (II) are defined in thesame way as in mode [7] above; R¹ denotes a group arbitrarily selectedfrom among a fluorine atom, a chlorine atom, a cyano group, a methylgroup, a trifluoromethyl group and a methoxy group; and R² denotes amethyl group], the manufacturing method including stages in which acompound represented by formula (AD-2) is obtained [these stages are thesame as (stage [7]-1) to (stage [7]-3) in mode [7] above; and thedefinitions of the substituent groups in the intermediates in (stage[7]-1) to (stage [7]-3) are the same as the definitions in mode [7-1]].

[7-2] A more preferred aspect of mode [7] is a method in which acompound represented by formula (AD-2) above is manufactured [in formula(AD-2), p, R¹, R² and ring A group represented by formula (II) aredefined in the same way as in mode [7-1] above; and R³ denotes afluorine atom], the manufacturing method including stages in which acompound represented by formula (AD-2) is obtained [these stages are thesame as (stage [7]-1) to (stage [7]-3) in mode [7] above; and thedefinitions of the substituent groups in the intermediates in (stage[7]-1) to (stage [7]-3) are the same as the definitions in mode [7-2]].

[7-3] A yet more preferred aspect of mode [7] is a method in which acompound represented by formula (AD-2) above is manufactured [in formula(AD-2), p, R¹, R² and R³ are defined in the same way as for mode [7-2]above; ring A group represented by formula (II) is a pyrimidin-4-ylgroup; and a more specific group obtained by combining the definitionsof p, R¹ and ring A group represented by formula (II) is a2,5-dimethylpyrimidin-4-yl group], the manufacturing method includingstages in which a compound represented by formula (AD-2) is obtained[these stages are the same as (stage [7]-1) to (stage [7]-3) in mode [7]above; and the definitions of the substituent groups in theintermediates in (stage [7]-1) to (stage [7]-3) are the same as thedefinitions in mode [7-3]].

[7a] Another aspect of the seventh mode of the present invention is amethod for manufacturing a compound represented by formula (AD-2) below:

[in formula (AD-2), p denotes an integer between 0 and 3; R¹ groups eachindependently denote a group arbitrarily selected from among a halogenatom, a cyano group, a C₁₋₆alkyl group, a C₃₋₈ cycloalkyl group, ahalogenated C₁₋₆alkyl group, a C₂₋₆ alkenyl group, a C₁₋₆ alkoxy group,a C₁₋₆ alkoxy-C₁₋₆ alkyl group, a hydroxy-C₁₋₆ alkyl group and a C₂₋₇alkanoyl group; R² denotes a C₁₋₆ alkyl group; R³ denotes a grouparbitrarily selected from among a hydrogen atom and a fluorine atom; andring A group represented by formula (II):

denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarilyselected from among a thiazol-2-yl group, a thiazol-4-yl group, a1-methyl-1H-imidazol-4-yl group, a 1,3,4-thiadiazol-2-yl group, a1,2,4-thiadiazol-5-yl group, a pyridin-2-yl group, a pyridazin-3-ylgroup, a pyrimidin-2-yl group, a pyrimidin-4-yl group and a pyrazin-2-ylgroup], the manufacturing method including stages in which a compoundrepresented by formula (ET-1):

[in formula (ET-1), p, R¹, R² and ring A group represented by formula(II) are defined in the same way as for formula (AD-2) in mode [7a];R^(D) denotes a group arbitrarily selected from among a C₁₋₆ alkylgroup, a C₆₋₁₄ aryl group and a C₇₋₂₀ aralkyl group (a routine methodfor manufacturing a compound represented by formula (ET-1) is describedlater)] is subjected to hydrolysis or hydrogenation (these are the sameas the reactions described in mode [6a] above) according to the type ofR^(D) group, thereby obtaining a compound represented by formula (CA-1):

[in formula (CA-1), p, R¹, R² and ring A group represented by formula(II) are defined in the same way as for formula (I) in mode [7a]] (stage[7a]-1), the compound represented by formula (CA-1) and a compoundrepresented by formula (PY-2):

[in formula (PY-2), R³ denotes a group arbitrarily selected from among ahydrogen atom and a fluorine atom; R^(C) denotes a group arbitrarilyselected from among a C₁₋₆ alkyl group, a C₆₋₁₄ aryl group and a C₇₋₂₀aralkyl group (a routine method for manufacturing a compound representedby formula (PY-2) is described later)] are reacted with each other inthe presence of a condensing agent (such as a condensing agent describedin mode [6a] above), in the presence or absence of a base such asN,N-diisopropylethylamine, triethylamine, pyridine or lutidine, in asolvent which does not take part in the reaction, such asdichloromethane, chloroform, diethyl ether, tetrahydrofuran, toluene,benzene, N,N-dimethylformamide, N-methylpyrrolidone, methanol, ethanolor 2-propanol at a temperature between 0° C. and a temperature at whichthe solvent refluxes, thereby obtaining a compound represented byformula (AD-4):

[in formula (AD-4), p, R¹, R², R³ and ring A group represented byformula (II) are defined in the same way as for formula (AD-2) in mode[7a]; and R^(C) denotes a group arbitrarily selected from among a C₁₋₆alkyl group, a C₆₋₁₄ aryl group and a C₇₋₂₀ aralkyl group] (stage[7a]-2), and a —C(═O)OR^(C) group (R^(C) denotes a group arbitrarilyselected from among a C₁₋₆ alkyl group, a C₆₋₁₄ aryl group and a C₇₋₂₀aralkyl group), which is a protecting group for an amino group informula (AD-4) is deprotected (according to the deprotection methoddescribed in mode [6] above) (stage [7a]-3), thereby obtaining thecompound represented by formula (AD-2).

[7a-1] A preferred aspect of mode [7a] is a method in which a compoundrepresented by formula (AD-2) above is manufactured [in formula (AD-2),p, R³ and ring A group represented by formula (II) are defined in thesame way as in mode [7a] above; R¹ denotes a group arbitrarily selectedfrom among a fluorine atom, a chlorine atom, a bromine atom, a cyanogroup, a methyl group, an ethyl group, an isopropyl group, a tert-butylgroup, a cyclopropyl group, a difluoromethyl group, a trifluoromethylgroup, a 1-hydroxyethyl group, a vinyl group, an acetyl group, a methoxygroup and an ethoxyethyl group; and R² denotes a methyl group], themanufacturing method including stages in which a compound represented byformula (AD-2) is obtained [these stages are the same as (stage [7a]-1)to (stage [7a]-3) in mode [7a] above; and the definitions of thesubstituent groups in the intermediates in (stage [7a]-1) to (stage[7a]-3) are the same as the definitions in mode [7a-1]].

[7a-2] A more preferred aspect of mode [7a] is a method in which acompound represented by formula (AD-2) above is manufactured [in formula(AD-2), p, R¹, R² and ring A group represented by formula (II) aredefined in the same way as in mode [7a-1] above; and R³ denotes afluorine atom], the manufacturing method including stages in which acompound represented by formula (AD-2) is obtained [these stages are thesame as (stage [7a]-1) to (stage [7a]-3) in mode [7a] above; and thedefinitions of the substituent groups in the intermediates in (stage[7a]-1) to (stage [7a]-3) are the same as the definitions in mode[7a-2]].

[7a-3] A yet more preferred aspect of mode [7a] is a method in which acompound represented by formula (AD-2) above is manufactured [in formula(AD-2), p, R¹, R² and R³ are defined in the same way as for mode [7a-2]above; ring A group represented by formula (II) is a thiazol-2-yl groupor a pyrimidin-4-yl group; and a more specific group obtained bycombining the definitions of p, R¹ and ring A group represented byformula (II) is a 4-(trifluoromethyl)thiazol-2-yl group, a5-fluoro-2-methoxypyrimidin-4-yl group, a 2,5-dimethylpyrimidin-4-ylgroup or a 2-methylpyrimidin-4-yl group], the manufacturing methodincluding stages in which a compound represented by formula (AD-2) isobtained [these stages are the same as (stage [7a]-1) to (stage [7a]-3)in mode [7a] above; and the definitions of the substituent groups in theintermediates in (stage [7a]-1) to (stage [7a]-3) are the same as thedefinitions in mode [7a-3]].

[8] An eighth mode of the present invention is a compound represented byformula (AD-1):

[in formula (AD-1), p denotes an integer between 0 and 3; R¹ groups eachindependently denote a group arbitrarily selected from among a halogenatom, a cyano group, a C₁₋₆alkyl group, a halogenated C₁₋₆ alkyl groupand a C₁₋₆alkoxy group; R² denotes a C₁₋₆ alkyl group; and ring A grouprepresented by formula (II):

denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarilyselected from among a pyridin-2-yl group, a pyridazin-3-yl group, apyrimidin-2-yl group, a pyrimidin-4-yl group and a pyrazin-2-yl group],or a salt of the compound, or a solvate of the compound or salt.

[8-1] A preferred aspect of mode [8] is a compound represented byformula (AD-1) above [in formula (AD-1), p and ring A group representedby formula (II) are defined in the same way as for mode [8] above; R¹denotes a group arbitrarily selected from among a fluorine atom, achlorine atom, a cyano group, a methyl group, a trifluoromethyl groupand a methoxy group; and R² denotes a methyl group], or a salt of thecompound, or a solvate of the compound or salt.

[8-2] A more preferred aspect of mode [8] is a compound represented byformula (AD-1) above [in formula (AD-1), p, R¹ and R² are defined in thesame way as for mode [8-1] above; ring A group represented by formula(II) is a pyrimidin-4-yl group; and a more specific group obtained bycombining the definitions of p, R¹ and ring A group represented byformula (II) is a 2,5-dimethylpyrimidin-4-yl group], or a salt of thecompound, or a solvate of the compound or salt.

[8a] Another aspect of the eighth mode of the present invention is acompound represented by formula (AD-1):

[in formula (AD-1), p denotes an integer between 0 and 3; R¹ groups eachindependently denote a group arbitrarily selected from among a halogenatom, a cyano group, a C₁₋₆ alkyl group, a C₃₋₈ cycloalkyl group, ahalogenated C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₁₋₆ alkoxy group,a C₁₋₆ alkoxy-C₁₋₆ alkyl group, a hydroxy-C₁₋₆ alkyl group and a C₂₋₇alkanoyl group; R² denotes a C₁₋₆ alkyl group; and ring A grouprepresented by formula (II):

denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarilyselected from among a thiazol-2-yl group, a thiazol-4-yl group, a1-methyl-1H-imidazol-4-yl group, a 1,3,4-thiadiazol-2-yl group, a1,2,4-thiadiazol-5-yl group, a pyridin-2-yl group, a pyridazin-3-ylgroup, a pyrimidin-2-yl group, a pyrimidin-4-yl group and a pyrazin-2-ylgroup], or a salt of the compound, or a solvate of the compound or salt.

[8a-1] A preferred aspect of mode [8a] is a compound represented byformula (AD-1) above [in formula (AD-1), p and ring A group representedby formula (II) are defined in the same way as for mode [8a] above; R¹denotes a group arbitrarily selected from among a fluorine atom, achlorine atom, a bromine atom, a cyano group, a methyl group, an ethylgroup, an isopropyl group, a tert-butyl group, a cyclopropyl group, adifluoromethyl group, a trifluoromethyl group, a 1-hydroxyethyl group, avinyl group, an acetyl group, a methoxy group and an ethoxyethyl group;and R² denotes a methyl group], or a salt of the compound, or a solvateof the compound or salt.

[8a-2] A more preferred aspect of mode [8a] is a compound represented byformula (AD-1) above [in formula (AD-1), p denotes an integer between 1and 3; R¹, R² and ring A group represented by formula (II) are definedin the same way as in mode [8a-1] above], or a salt of the compound, ora solvate of the compound or salt.

[8a-3] A yet more preferred aspect of mode [8a] is a compoundrepresented by formula (AD-1) above [in formula (AD-1), p, R¹ and R² aredefined in the same way as for mode [8a-2] above; ring A grouprepresented by formula (II) is a thiazol-2-yl group or a pyrimidin-4-ylgroup; and a more specific group obtained by combining the definitionsof p, R¹ and ring A group represented by formula (II) is a4-(trifluoromethyl)thiazol-2-yl group, a5-fluoro-2-methoxypyrimidin-4-yl group, a 2,5-dimethylpyrimidin-4-ylgroup or a 2-methylpyrimidin-4-yl group], or a salt of the compound, ora solvate of the compound or salt.

[8′]

Mode no. 8′ of the present invention lists the intermediate compoundsshown below as preferred intermediate compounds for compoundsrepresented by formula (AD-1) in modes [8] to [8-3] above or modes [8a]to [8a-3] above, or salts of these intermediate compounds, or solvatesof the intermediate compounds or salts. The listed intermediatecompounds are obtained in steps having working example numberscorresponding to the compound names. For example, Working Example Number1-2 means that an intermediate compound corresponding to <Step 2> inWorking Example 1 is obtained. Moreover, the names of the compoundsshown below are based on English names obtained using the Cambridge SoftChem BioDraw Ultra 12.0.2.1076 compound nomenclature program.

TABLE 1 Working Example Compound No. 4-(2,5-dimethylpyrimidin-4-yl)-1- 2and 6-1 methyl-1H-pyrazole-5-carboxamde1-methyl-4-(2-methylpyrimidin-4-yl)-1H- 9 pyrazole-5-carboxamide4-(5-fluoro-2-methoxypyrimidin-4-yl)-1- 13methyl-1H-pyrazole-5-carboxamide 1-methyl-4-(4-(trifluoromethyl)thiazol-17 2-yl)-1H-pyrazole-5-carboxamide

[9] A ninth mode of the present invention is a compound represented byformula (AD-2):

[in formula (AD-2), p denotes an integer between 0 and 3; R¹ groups eachindependently denote a group arbitrarily selected from among a halogenatom, a cyano group, a C₁₋₆ alkyl group, a halogenated C₁₋₆ alkyl groupand a C₁₋₆ alkoxy group; R² denotes a C₁₋₆ alkyl group; R³ denotes agroup arbitrarily selected from among a hydrogen atom and a fluorineatom; and ring A group represented by formula (II):

denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarilyselected from among a pyridin-2-yl group, a pyridazin-3-yl group, apyrimidin-2-yl group, a pyrimidin-4-yl group and a pyrazin-2-yl group],or a salt of the compound, or a solvate of the compound or salt.

[9-1] A preferred aspect of mode [9] is a compound represented byformula (AD-2) above [in formula (AD-2), p, R³ and ring A grouprepresented by formula (II) are defined in the same way as for mode [9]above; R¹ denotes a group arbitrarily selected from among a fluorineatom, a chlorine atom, a cyano group, a methyl group, a trifluoromethylgroup and a methoxy group; and R² denotes a methyl group], or a salt ofthe compound, or a solvate of the compound or salt.

[9-2] A more preferred aspect of mode [9] is a compound represented byformula (AD-2) above [in formula (AD-2), p, R¹, R² and ring A grouprepresented by formula (II) are defined in the same way as for mode[9-1] above; and R³ denotes a fluorine atom], or a salt of the compound,or a solvate of the compound or salt.

[9-3] A yet more preferred aspect of mode [9] is a compound representedby formula (AD-2) above [in formula (AD-2), p, R¹, R² and R³ are definedin the same way as for mode [9-2] above; ring A group represented byformula (II) is a pyrimidin-4-yl group; and a more specific groupobtained by combining the definitions of p, R¹ and ring A grouprepresented by formula (II) is a 2,5-dimethylpyrimidin-4-yl group], or asalt of the compound, or a solvate of the compound or salt.

[9a] Another aspect of the ninth mode of the present invention is acompound represented by formula (AD-2):

[in formula (AD-2), p denotes an integer between 0 and 3; R¹ groups eachindependently denote a group arbitrarily selected from among a halogenatom, a cyano group, a C₁₋₆ alkyl group, a C₃₋₈ cycloalkyl group, ahalogenated C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₁₋₆ alkoxy group,a C₁₋₆ alkoxy-C₁₋₆ alkyl group, a hydroxy-C₁₋₆ alkyl group and a C₂₋₇alkanoyl group; R² denotes a C₁₋₆ alkyl group; R³ denotes a grouparbitrarily selected from among a hydrogen atom and a fluorine atom; andring A group represented by formula (II):

denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarilyselected from among a thiazol-2-yl group, a thiazol-4-yl group, a1-methyl-1H-imidazol-4-yl group, a 1,3,4-thiadiazol-2-yl group, a1,2,4-thiadiazol-5-yl group, a pyridin-2-yl group, a pyridazin-3-ylgroup, a pyrimidin-2-yl group, a pyrimidin-4-yl group and a pyrazin-2-ylgroup], or a salt of the compound, or a solvate of the compound or salt.

[9a-1] A preferred aspect of mode [9a] is a compound represented byformula (AD-2) above [in formula (AD-2), p, R³ and ring A grouprepresented by formula (II) are defined in the same way as for mode [9a]above; R¹ denotes a group arbitrarily selected from among a fluorineatom, a chlorine atom, a bromine atom, a cyano group, a methyl group, anethyl group, an isopropyl group, a tert-butyl group, a cyclopropylgroup, a difluoromethyl group, a trifluoromethyl group, a 1-hydroxyethylgroup, a vinyl group, an acetyl group, a methoxy group and anethoxyethyl group; and R² denotes a methyl group], or a salt of thecompound, or a solvate of the compound or salt.

[9a-2] A more preferred aspect of mode [9a] is a compound represented byformula (AD-2) above [in formula (AD-2), p, R¹, R² and ring A grouprepresented by formula (II) are defined in the same way as for mode[9a-1] above; and R³ denotes a fluorine atom], or a salt of thecompound, or a solvate of the compound or salt.

[9a-3] A yet more preferred aspect of mode [9a] is a compoundrepresented by formula (AD-2) above [in formula (AD-2), p, R¹, R² and R³are defined in the same way as for mode [9a-2] above; ring A grouprepresented by formula (II) is a thiazol-2-yl group or a pyrimidin-4-ylgroup; and a more specific group obtained by combining the definitionsof p, R¹ and ring A group represented by formula (II) is a4-(trifluoromethyl)thiazol-2-yl group, a5-fluoro-2-methoxypyrimidin-4-yl group, a 2,5-dimethylpyrimidin-4-ylgroup or a 2-methylpyrimidin-4-yl group], or a salt of the compound, ora solvate of the compound or salt.

[9′]

Mode no. 9′ of the present invention lists the intermediate compoundsshown below as preferred intermediate compounds for compoundsrepresented by formula (AD-2) in modes [9] to [9-3] above or modes [9a]to [9a-3] above, or salts of these intermediate compounds, or solvatesof the intermediate compounds or salts. The listed intermediatecompounds are obtained in steps having working example numberscorresponding to the compound names. Explanations relating to the namesof the compounds and the working example numbers are the same as theexplanations given in mode [8′] above.

TABLE 2 Working Example Compound No. N-(2-amino-5-fluoropyridin-4-yl)-4-5-3 and 6-2 (2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide N-(2-amino-5-fluoropyridin-4-yl)-4-(2- 10-1methylpyrimidin-4-yl)-1-methyl-1H- pyrazole-5-carboxamideN-(2-amino-5-fluoropyridin-4-yl)-4-(5- 14-1fluoro-2-methoxypyrimidin-4-yl)-1- methyl-1H-pyrazole-5-carboxamideN-(2-amino-5-fluoropyridin-4-yl)-4-(4- 18-1(trifluoromethyl)thiazol-2-yl)-1- methyl-1H-pyrazole-5-carboxamide

[10] A tenth mode of the present invention is a compound represented byformula (AD-3):

[in formula (AD-3), p denotes an integer between 0 and 3; q denotes aninteger between 0 and 2; R¹ groups each independently denote a grouparbitrarily selected from among a halogen atom, a cyano group, a C₁₋₆alkyl group, a halogenated C₁₋₆ alkyl group and a C₁₋₆ alkoxy group; R²denotes a C₁₋₆ alkyl group; R³ denotes a group arbitrarily selected fromamong a hydrogen atom and a fluorine atom; R⁴ groups each independentlydenote a group arbitrarily selected from among a halogen atom, a C₁₋₆alkyl group and a C₁₋₆ alkoxy group; and ring A group represented byformula (II):

denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarilyselected from among a pyridin-2-yl group, a pyridazin-3-yl group, apyrimidin-2-yl group, a pyrimidin-4-yl group and a pyrazin-2-yl group],or a salt of the compound, or a solvate of the compound or salt.

[10-1] A preferred aspect of mode [10] is a compound represented byformula (AD-3) above [in formula (AD-3), p, q, R³ and ring A grouprepresented by formula (II) are defined in the same way as for mode [10]above; R¹ denotes a group arbitrarily selected from among a fluorineatom, a chlorine atom, a cyano group, a methyl group, a trifluoromethylgroup and a methoxy group; R² denotes a methyl group; and R⁴ denotes agroup arbitrarily selected from among a fluorine atom, a methyl groupand a methoxy group], or a salt of the compound, or a solvate of thecompound or salt.

[10-2] A more preferred aspect of mode [10] is a compound represented byformula (AD-3) above [in formula (AD-3), p, R¹, R², R⁴ and ring A grouprepresented by formula (II) are defined in the same way as for mode[10-1] above; q denotes the integer 0; and R³ denotes a fluorine atom],or a salt of the compound, or a solvate of the compound or salt.

[10-3] A yet more preferred aspect of mode [10] is a compoundrepresented by formula (AD-3) above [in formula (AD-3), p, q, R¹, R², R³and R⁴ are defined in the same way as for mode [10-2] above; ring Agroup represented by formula (II) is a pyrimidin-4-yl group; and a morespecific group obtained by combining the definitions of p, R¹ and ring Agroup represented by formula (II) is a 2,5-dimethylpyrimidin-4-ylgroup], or a salt of the compound, or a solvate of the compound or salt.

[10a] Another aspect of the tenth mode of the present invention is acompound represented by formula (AD-3):

[in formula (AD-3), p denotes an integer between 0 and 3; q denotes aninteger between 0 and 2; R¹ groups each independently denote a grouparbitrarily selected from among a halogen atom, a cyano group, a C₁₋₆alkyl group, a C₃₋₈ cycloalkyl group, a halogenated C₁₋₆ alkyl group, aC₂₋₆ alkenyl group, a C₁₋₆ alkoxy group, a C₁₋₆ alkoxy-C₁₋₆ alkyl group,a hydroxy-C₁₋₆ alkyl group and a C₂₋₇ alkanoyl group; R² denotes a C₁₋₆alkyl group; R³ denotes a group arbitrarily selected from among ahydrogen atom and a fluorine atom; R⁴ groups each independently denote agroup arbitrarily selected from among a halogen atom, a C₁₋₆ alkyl groupand a C₁₋₆ alkoxy group; and ring A group represented by formula (II):

denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarilyselected from among a thiazol-2-yl group, a thiazol-4-yl group, a1-methyl-1H-imidazol-4-yl group, a 1,3,4-thiadiazol-2-yl group, a1,2,4-thiadiazol-5-yl group, a pyridin-2-yl group, a pyridazin-3-ylgroup, a pyrimidin-2-yl group, a pyrimidin-4-yl group and a pyrazin-2-ylgroup], or a salt of the compound, or a solvate of the compound or salt.

[10a-1] A preferred aspect of mode [10a] is a compound represented byformula (AD-3) above [in formula (AD-3), p, q, R³ and ring A grouprepresented by formula (II) are defined in the same way as for mode[10a] above; R¹ denotes a group arbitrarily selected from among afluorine atom, a chlorine atom, a bromine atom, a cyano group, a methylgroup, an ethyl group, an isopropyl group, a tert-butyl group, acyclopropyl group, a difluoromethyl group, a trifluoromethyl group, a1-hydroxyethyl group, a vinyl group, an acetyl group, a methoxy groupand an ethoxyethyl group; R² denotes a methyl group; and R⁴ denotes agroup arbitrarily selected from among a fluorine atom, a methyl groupand a methoxy group], or a salt of the compound, or a solvate of thecompound or salt.

[10a-2] A more preferred aspect of mode [10a] is a compound representedby formula (AD-3) above [in formula (AD-3), p, R¹, R², R⁴ and ring Agroup represented by formula (II) are defined in the same way as formode [10a-1] above; q denotes the integer 0; and R³ denotes a fluorineatom], or a salt of the compound, or a solvate of the compound or salt.

[10a-3] A yet more preferred aspect of mode [10a] is a compoundrepresented by formula (AD-3) above [in formula (AD-3), p, q, R¹, R², R³and R⁴ are defined in the same way as for mode [10a-2] above; ring Agroup represented by formula (II) is a thiazol-2-yl group or apyrimidin-4-yl group; and a more specific group obtained by combiningthe definitions of p, R¹ and ring A group represented by formula (II) isa 4-(trifluoromethyl)thiazol-2-yl group, a5-fluoro-2-methoxypyrimidin-4-yl group, a 2,5-dimethylpyrimidin-4-ylgroup or a 2-methylpyrimidin-4-yl group], or a salt of the compound, ora solvate of the compound or salt.

[10′]

Mode no. 10′ of the present invention lists the intermediate compoundsshown below as preferred intermediate compounds for compoundsrepresented by formula (AD-3) in modes [10] to [10-3] above or modes[10a] to [10a-3] above, or salts of these intermediate compounds, orsolvates of the intermediate compounds or salts. The listed intermediatecompounds are obtained in steps having working example numberscorresponding to the compound names. Explanations relating to the namesof the compounds and the working example numbers are the same as theexplanations given in mode [8′] above.

TABLE 3 Working Example Compound No.N-(benzimidamido-5-fluoropyridin-4-yl)-  6-34-(2,5-dimethylpyrimidin-4-yl)-1- methyl-1H-pyrazole-5-carboxamideN-(benzimidamido-5-fluoropyridin-4-yl)- 10-24-(2-methylpyrimidin-4-yl)-1-methyl-1H- pyrazole-5-carboxamideN-(benzimidamido-5-fluoropyridin-4-yl)- 14-24-(5-fluoro-2-methoxypyrimidin-4-yl)-1- methyl-1H-pyrazole-5-carboxamideN-(benzimidamido-5-fluoropyridin-4-yl)- 18-24-(4-(trifluoromethyl)thiazol-2-yl)-1- methyl-1H-pyrazole-5-carboxamide

[11] An eleventh mode of the present invention is a compound representedby formula (PY-1-1):

or a salt of the compound, or a solvate of the compound or salt.

[12] A twelfth mode of the present invention is a compound representedby formula (PY-2-1):

[in formula (PY-2), R^(C) denotes a group arbitrarily selected fromamong a C₁₋₆ alkyl group, a C₆₋₁₄ aryl group and a C₇₋₂₀ aralkyl group],or a salt of the compound, or a solvate of the compound or salt.

[12-1] A preferred aspect of mode [12] is a compound represented byformula (PY-2-1) above [in formula (PY-2), R^(C) denotes a benzylgroup], or a salt of the compound, or a solvate of the compound or salt.

[13] A thirteenth mode of the present invention is a compoundrepresented by formula (ET-1):

[in formula (ET-1), p denotes an integer between 0 and 3; R¹ groups eachindependently denote a group arbitrarily selected from among a halogenatom, a cyano group, a C₁₋₆ alkyl group, a halogenated C₁₋₆ alkyl groupand a C₁₋₆ alkoxy group; R² denotes a C₁₋₆ alkyl group; R^(D) groupseach independently denote a group arbitrarily selected from among a C₁₋₆alkyl group, a C₆₋₁₄ aryl group and a C₇₋₂₀ aralkyl group; and ring Agroup represented by formula (II):

denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarilyselected from among a pyridin-2-yl group, a pyridazin-3-yl group, apyrimidin-2-yl group, a pyrimidin-4-yl group and a pyrazin-2-yl group],or a salt of the compound, or a solvate of the compound or salt.

[13-1] A preferred aspect of mode [13] is a compound represented byformula (ET-1) above [in formula (ET-1), p denotes an integer between 0and 3; R¹ groups each independently denote a group arbitrarily selectedfrom among a fluorine atom, a chlorine atom, a bromine atom, a cyanogroup, a methyl group, an ethyl group, an isopropyl group, a tert-butylgroup, a cyclopropyl group, a difluoromethyl group, a trifluoromethylgroup, a 1-hydroxyethyl group, a vinyl group, an acetyl group, a methoxygroup and an ethoxyethyl group; R² denotes a methyl group; R^(D) groupseach independently denote a group arbitrarily selected from among amethyl group, an ethyl group, a tert-butyl group, a phenyl group and abenzyl group; and ring A group represented by formula (II) is defined inthe same way as in mode [13] above], or a salt of the compound, or asolvate of the compound or salt.

[13-2] A more preferred aspect of mode [13] is a compound represented byformula (ET-1) above [in formula (ET-1), p denotes an integer between 1and 3; R¹, R², R^(D) and ring A group represented by formula (II) aredefined in the same way as in mode [13-1] above], or a salt of thecompound, or a solvate of the compound or salt.

[13-3] A preferred aspect of mode [13] is a compound represented byformula (ET-1) above [in formula (ET-1), p, R¹, R², R^(D) and ring Agroup represented by formula (II) are defined in the same way as in mode[13-2] above; and a more specific group obtained by combining thedefinitions of p, R¹ and ring A group is a 2,5-dimethylpyrimidin-4-ylgroup], or a salt of the compound, or a solvate of the compound or salt.

[13a] Another aspect of the thirteenth mode of the present invention isa compound represented by formula (ET-1) below:

[in formula (ET-1), p denotes an integer between 0 and 3; R¹ groups eachindependently denote a group arbitrarily selected from among a halogenatom, a cyano group, a C₁₋₆ alkyl group, a C₃₋₈ cycloalkyl group, ahalogenated C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₁₋₆ alkoxy group,a C₁₋₆ alkoxy-C₁₋₆ alkyl group, a hydroxy-C₁₋₆ alkyl group and a C₂₋₇alkanoyl group; R² denotes a C₁₋₆ alkyl group; R^(D) denotes a grouparbitrarily selected from among a C₁₋₆ alkyl group, a C₆₋₁₄ aryl groupand a C₇₋₂₀ aralkyl group; and ring A group represented by formula (II):

denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarilyselected from among a thiazol-2-yl group, a thiazol-4-yl group, a1-methyl-1H-imidazol-4-yl group, a 1,3,4-thiadiazol-2-yl group, a1,2,4-thiadiazol-5-yl group, a pyridin-2-yl group, a pyridazin-3-ylgroup, a pyrimidin-2-yl group, a pyrimidin-4-yl group and a pyrazin-2-ylgroup], or a salt of the compound, or a solvate of the compound or salt.

[13a-1] A preferred aspect of mode [13a] is a compound represented byformula (ET-1) above [in formula (ET-1), p denotes an integer between 0and 3; R¹ denotes a group arbitrarily selected from among a fluorineatom, a chlorine atom, a bromine atom, a cyano group, a methyl group, anethyl group, an isopropyl group, a tert-butyl group, a cyclopropylgroup, a difluoromethyl group, a trifluoromethyl group, a 1-hydroxyethylgroup, a vinyl group, an acetyl group, a methoxy group and anethoxyethyl group; R² denotes a methyl group; R^(D) groups eachindependently denote a group arbitrarily selected from among a methylgroup, an ethyl group, a tert-butyl group, a phenyl group and a benzylgroup; and ring A group represented by formula (II) is defined in thesame way as in mode [13a] above], or a salt of the compound, or asolvate of the compound or salt.

[13a-2] A more preferred aspect of mode [13a] is a compound representedby formula (ET-1) above [in formula (ET-1), p denotes an integer between1 and 3; R¹, R², R^(D) and ring A group represented by formula (II) aredefined in the same way as in mode [13a-1] above], or a salt of thecompound, or a solvate of the compound or salt.

[13a-3] A yet more preferred aspect of mode [13a] is a compoundrepresented by formula (ET-1) above [in formula (ET-1), p, R¹, R² andR^(D) are defined in the same way as in mode [13a-2] above; ring A grouprepresented by formula (II) is a thiazol-2-yl group or a pyrimidin-4-ylgroup; and a more specific group obtained by combining the definitionsof p, R¹ and ring A group represented by formula (II) is a4-(trifluoromethyl)thiazol-2-yl group, a5-fluoro-2-methoxypyrimidin-4-yl group, a 2,5-dimethylpyrimidin-4-ylgroup or a 2-methylpyrimidin-4-yl group], or a salt of the compound, ora solvate of the compound or salt.

[13′]

Mode no. 13′ of the present invention lists the intermediate compoundsshown below as preferred intermediate compounds for compoundsrepresented by formula (ET-1) in modes [13] to [13-3] above or modes[13a] to [13a-3] above, or salts of these intermediate compounds, orsolvates of the intermediate compounds or salts. The listed intermediatecompounds are obtained in steps having working example numberscorresponding to the compound names. Explanations relating to the namesof the compounds and the working example numbers are the same as theexplanations given in mode [8′] above.

TABLE 4 Working Example Compound No. Ethyl4-(2,5-dimethylpyrimidin-4-yl)-1- 1 methyl-1H-pyrazole-5-carboxylateMethyl 1-methyl-4-(2-methylpyrimidin-4- 7 yl)-1H-pyrazole-5-carboxylateMethyl 4-(5-fluoro-2-methoxypyrimidin- 11 4-yl)-1-methyl-1H-pyrazole-5-carboxylate Methyl 1-methyl-4-(4- 15-2(trifluoromethyl)thiazol-2-yl)-1H- pyrazole-5-carboxylate

[14] A fourteenth mode of the present invention is a compoundrepresented by formula (CA-1):

[in formula (CA-1), p denotes an integer between 0 and 3; R¹ groups eachindependently denote a group arbitrarily selected from among a halogenatom, a cyano group, a C₁₋₆ alkyl group, a halogenated C₁₋₆ alkyl groupand a C₁₋₆ alkoxy group; R² denotes a C₁₋₆ alkyl group; and ring A grouprepresented by formula (II):

denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarilyselected from among a pyridin-2-yl group, a pyridazin-3-yl group, apyrimidin-2-yl group, a pyrimidin-4-yl group and a pyrazin-2-yl group],or a salt of the compound, or a solvate of the compound or salt.

[14-1] A preferred aspect of mode [14] is a compound represented byformula (CA-1) above [in formula (CA-1), p denotes an integer between 0and 3; R¹ groups each independently denote a group arbitrarily selectedfrom among a fluorine atom, a chlorine atom, a bromine atom, a cyanogroup, a methyl group, an ethyl group, an isopropyl group, a tert-butylgroup, a cyclopropyl group, a difluoromethyl group, a trifluoromethylgroup, a 1-hydroxyethyl group, a vinyl group, an acetyl group, a methoxygroup and an ethoxyethyl group; R² denotes a methyl group; and ring Agroup represented by formula (II) is defined in the same way as in mode[14] above], or a salt of the compound, or a solvate of the compound orsalt.

[14-2] A more preferred aspect of mode [14] is a compound represented byformula (CA-1) above [in formula (CA-1), p denotes an integer between 1and 3; R¹, R² and ring A group represented by formula (II) are definedin the same way as in mode [14-1] above], or a salt of the compound, ora solvate of the compound or salt.

[14-3] A preferred aspect of mode [14] is a compound represented byformula (CA-1) above [in formula (CA-1), p, R¹, R² and ring A grouprepresented by formula (II) are defined in the same way as in mode[14-2] above; and a more specific group obtained by combining thedefinitions of p, R¹ and ring A group is a 2,5-dimethylpyrimidin-4-ylgroup], or a salt of the compound, or a solvate of the compound or salt.

[14a] Another aspect of the fourteenth mode of the present invention isa compound represented by formula (CA-1) below:

[in formula (CA-1), p denotes an integer between 0 and 3; R¹ groups eachindependently denote a group arbitrarily selected from among a halogenatom, a cyano group, a C₁₋₆ alkyl group, a C₃₋₈ cycloalkyl group, ahalogenated C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₁₋₆ alkoxy group,a C₁₋₆ alkoxy-C₁₋₆ alkyl group, a hydroxy-C₁₋₆ alkyl group and a C₂₋₇alkanoyl group; R² denotes a C₁₋₆ alkyl group; and ring A grouprepresented by formula (II):

denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarilyselected from among a thiazol-2-yl group, a thiazol-4-yl group, a1-methyl-1H-imidazol-4-yl group, a 1,3,4-thiadiazol-2-yl group, a1,2,4-thiadiazol-5-yl group, a pyridin-2-yl group, a pyridazin-3-ylgroup, a pyrimidin-2-yl group, a pyrimidin-4-yl group and a pyrazin-2-ylgroup], or a salt of the compound, or a solvate of the compound or salt.

[14a-1] A preferred aspect of mode [14a] is a compound represented byformula (CA-1) above [in formula (CA-1), p denotes an integer between 0and 3; R¹ denotes a group arbitrarily selected from among a fluorineatom, a chlorine atom, a bromine atom, a cyano group, a methyl group, anethyl group, an isopropyl group, a tert-butyl group, a cyclopropylgroup, a difluoromethyl group, a trifluoromethyl group, a 1-hydroxyethylgroup, a vinyl group, an acetyl group, a methoxy group and anethoxyethyl group; R² denotes a methyl group; and ring A grouprepresented by formula (II) is defined in the same way as in mode [14a]above], or a salt of the compound, or a solvate of the compound or salt.

[14a-2] A more preferred aspect of mode [14a] is a compound representedby formula (CA-1) above [in formula (CA-1), p denotes an integer between1 and 3; R¹, R² and ring A group represented by formula (II) are definedin the same way as in mode [14a-1] above], or a salt of the compound, ora solvate of the compound or salt.

[14a-3] A yet more preferred aspect of mode [14a] is a compoundrepresented by formula (CA-1) above [in formula (CA-1), p, R¹ and R² aredefined in the same way as in mode [14a-2] above; ring A grouprepresented by formula (II) is a thiazol-2-yl group or a pyrimidin-4-ylgroup; and a more specific group obtained by combining the definitionsof p, R¹ and ring A group represented by formula (II) is a4-(trifluoromethyl)thiazol-2-yl group, a5-fluoro-2-methoxypyrimidin-4-yl group, a 2,5-dimethylpyrimidin-4-ylgroup or a 2-methylpyrimidin-4-yl group], or a salt of the compound, ora solvate of the compound or salt.

[14′]

Mode no. 14′ of the present invention lists the intermediate compoundsshown below as preferred intermediate compounds for compoundsrepresented by formula (CA-1) in modes [14] to [14-3] above or modes[14a] to [14a-3] above, or salts of these intermediate compounds, orsolvates of the intermediate compounds or salts. The listed intermediatecompounds are obtained in steps having working example numberscorresponding to the compound names. Explanations relating to the namesof the compounds and the working example numbers are the same as theexplanations given in mode [8′] above.

TABLE 5 Working Example Compound No. 4-(2,5-dimethylpyrimidin-4-yl)-1-5-1 methyl-1H-pyrazole-5-carboxylic acid1-methyl-4-(2-methylpyrimidin-4-yl)-1H- 8 pyrazole-5-carboxylic acid4-(5-fluoro-2-methoxypyrimidin-4-yl)-1- 12methyl-1H-pyrazole-5-carboxylic acid1-methyl-4-(4-(trifluoromethyl)thiazol- 162-yl)-1H-pyrazole-5-carboxylic acid

[15] A fifteenth mode of the present invention is a method formanufacturing a compound represented by formula (I) below:

[in formula (I), p denotes an integer between 0 and 3; q denotes aninteger between 0 and 2; R¹ groups each independently denote a grouparbitrarily selected from among a halogen atom, a cyano group, a C₁₋₆alkyl group, a C₃₋₈ cycloalkyl group, a halogenated C₁₋₆ alkyl group, aC₂₋₆ alkenyl group, a C₁₋₆ alkoxy group, a C₁₋₆ alkoxy-C₁₋₆ alkyl group,a hydroxy-C₁₋₆ alkyl group and a C₂₋₇ alkanoyl group; R² denotes a C₁₋₆alkyl group; R³ denotes a group arbitrarily selected from among ahydrogen atom and a fluorine atom; R⁴ groups each independently denote agroup arbitrarily selected from among a halogen atom, a C₁₋₆ alkyl groupand a C₁₋₆ alkoxy group; and ring A group represented by formula (II):

denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarilyselected from among a thiazol-2-yl group, a thiazol-4-yl group, a1-methyl-1H-imidazol-4-yl group, a 1,3,4-thiadiazol-2-yl group, a1,2,4-thiadiazol-5-yl group, a pyridin-2-yl group, a pyridazin-3-ylgroup, a pyrimidin-2-yl group, a pyrimidin-4-yl group and a pyrazin-2-ylgroup], the manufacturing method including stages in which a compoundrepresented by formula (AD-1):

[in formula (AD-1), p, R¹, R² and ring A group represented by formula(II) are defined in the same way as for formula (I) in mode [15]] and a2-amino-4-iodopyridine derivative represented by formula (PY-1):

[in formula (PY-1), R³ denotes a hydrogen atom or a fluorine atom (aroutine method for manufacturing a compound represented by formula(PY-1) is described later)] are reacted with each other in the presenceof N,N-dimethyl-1,2-ethanediamine, copper iodide (CuI) and an inorganicbase such as potassium carbonate or potassium phosphate using a solventwhich does not take part in the reaction, such as 1,4-dioxane,tetrahydrofuran or 1,2-dimethoxyethane, at a temperature between 0° C.and a temperature at which the solvent refluxes, thereby obtaining acompound represented by formula (AD-2):

[in formula (AD-2), p, R¹, R², R³ and ring A group represented byformula (II) are defined in the same way as for formula (I) in mode[15]] (stage [15]-1), the compound represented by formula (AD-2) and acompound represented by formula (IM-1):

[in formula (IM-1), q and R⁴ are defined in the same way as for formula(I) in mode [15]; and R^(B) denotes a C₁₋₆ alkyl group] or a saltthereof (the compound represented by formula (IM-1) and salt thereof arecommercially available compounds or compounds that can be easilyobtained from commercially available compounds using manufacturingmethods known from literature) are reacted with each other using asolvent which does not take part in the reaction, such as dimethylsulfoxide or pyridine, at a temperature between 0° C. and a temperatureat which the solvent refluxes, thereby obtaining a compound representedby formula (AD-3):

[in formula (AD-3), p, q, R¹, R², R³, R⁴ and ring A group represented byformula (II) are defined in the same way as for formula (I) in mode[15]] (stage [15]-2), and the compound represented by formula (AD-3) issubjected to a cyclization reaction in the presence of air using asolvent which does not take part in the reaction, such as dimethylsulfoxide (DMSO) or N-methylpyrrolidone (NMP), at a temperature between0° C. and a temperature at which the solvent refluxes in the presence ofa copper reagent such as copper iodide (CuI) or copper chloride (CuCl)(stage [15]-3), thereby obtaining the compound represented by formula(I).

[15-1] A preferred aspect of mode [15] is a method in which a compoundrepresented by formula (I) above is manufactured [in formula (I), p, q,R³ and ring A group represented by formula (II) are defined in the sameway as in mode [15] above; R¹ denotes a group arbitrarily selected fromamong a fluorine atom, a chlorine atom, a bromine atom, a cyano group, amethyl group, an ethyl group, an isopropyl group, a tert-butyl group, acyclopropyl group, a difluoromethyl group, a trifluoromethyl group, a1-hydroxyethyl group, a vinyl group, an acetyl group, a methoxy groupand an ethoxyethyl group; R² denotes a methyl group; and R⁴ denotes agroup arbitrarily selected from among a fluorine atom, a methyl groupand a methoxy group], the manufacturing method including stages in whicha compound represented by formula (I) is obtained [these stages are thesame as (stage [15]-1) to (stage [15]-3) in mode [15] above; thedefinitions of the substituent groups in the intermediates in (stage[15]-1) to (stage [15]-3) are the same as the definitions in mode[15-1], and R^(B) in formula (IM-1) is a C₁₋₆ alkyl group].

[15-2] A more preferred aspect of mode [15] is a method in which acompound represented by formula (I) above is manufactured [in formula(I), p, R¹, R², R⁴ and ring A group represented by formula (II) aredefined in the same way as for mode [15-1] above; q denotes the integer0; and R³ denotes a fluorine atom], the manufacturing method includingstages in which a compound represented by formula (I) is obtained [thesestages are the same as (stage [15]-1) to (stage [15]-3) in mode [15]above; the definitions of the substituent groups in the intermediates in(stage [15]-1) to (stage [15]-3) are the same as the definitions in mode[15-2], and R^(B) in formula (IM-1) is a C₁₋₆ alkyl group].

[15-3] A yet more preferred aspect of mode [15] is a method in which acompound represented by formula (I) above is manufactured [in formula(I), p, q, R¹, R², R³ and R⁴ are defined in the same way as for mode[15-2] above; ring A group represented by formula (II) is a thiazol-2-ylgroup or a pyrimidin-4-yl group; and a more specific group obtained bycombining the definitions of p, R¹ and ring A group represented byformula (II) is a 4-(trifluoromethyl)thiazol-2-yl group, a5-fluoro-2-methoxypyrimidin-4-yl group, a 2,5-dimethylpyrimidin-4-ylgroup or a 2-methylpyrimidin-4-yl group], the manufacturing methodincluding stages in which a compound represented by formula (I) isobtained [these stages are the same as (stage [15]-1) to (stage [15]-3)in mode [15] above; the definitions of the substituent groups in theintermediates in (stage [15]-1) to (stage [15]-3) are the same as thedefinitions in mode [15-3], and R^(B) in formula (IM-1) is a C₁₋₆ alkylgroup].

[16] A sixteenth mode of the present invention is a method formanufacturing a compound represented by formula (AD-3) below:

[in formula (AD-3), p denotes an integer between 0 and 3; q denotes aninteger between 0 and 2; R¹ groups each independently denote a grouparbitrarily selected from among a halogen atom, a cyano group, a C₁₋₆alkyl group, a C₃₋₈ cycloalkyl group, a halogenated C₁₋₆ alkyl group, aC₂₋₆ alkenyl group, a C₁₋₆ alkoxy group, a C₁₋₆ alkoxy-C₁₋₆ alkyl group,a hydroxy-C₁₋₆ alkyl group and a C₂₋₇ alkanoyl group; R² denotes a C₁₋₆alkyl group; R³ denotes a hydrogen atom or a fluorine atom; R⁴ groupseach independently denote a group arbitrarily selected from among ahalogen atom, a C₁₋₆ alkyl group and a C₁₋₆ alkoxy group; and ring Agroup represented by formula (II):

denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarilyselected from among a thiazol-2-yl group, a thiazol-4-yl group, a1-methyl-1H-imidazol-4-yl group, a 1,3,4-thiadiazol-2-yl group, a1,2,4-thiadiazol-5-yl group, a pyridin-2-yl group, a pyridazin-3-ylgroup, a pyrimidin-2-yl group, a pyrimidin-4-yl group and a pyrazin-2-ylgroup], the manufacturing method including stages in which a compoundrepresented by formula (AD-1):

[in formula (AD-1), p, R¹, R² and ring A group represented by formula(II) are defined in the same way as for formula (AD-3) in mode [16]] anda 2-amino-4-iodopyridine derivative represented by formula (PY-1):

[in formula (PY-1), R³ denotes a group arbitrarily selected from among ahydrogen atom and a fluorine atom (a routine method for manufacturing acompound represented by formula (PY-1) is described later)] are reactedwith each other in the presence of N,N-dimethyl-1,2-ethanediamine,copper iodide (CuI) and an inorganic base such as potassium carbonate orpotassium phosphate using a solvent which does not take part in thereaction, such as 1,4-dioxane, tetrahydrofuran or 1,2-dimethoxyethane,at a temperature between 0° C. and a temperature at which the solventrefluxes, thereby obtaining a compound represented by formula (AD-2):

[in formula (AD-2), p, R¹, R², R³ and ring A group represented byformula (II) are defined in the same way as for formula (AD-3) in mode[16]] (stage [16]-1), and the compound represented by formula (AD-2) anda compound represented by formula (IM-1):

[in formula (IM-1), q and R⁴ are defined in the same way as for formula(AD-3) in mode [16]; and R^(B) denotes a C₁₋₆ alkyl group] or a saltthereof (the compound represented by formula (IM-1) and salt thereof arecommercially available compounds or compounds that can be easilyobtained from commercially available compounds using manufacturingmethods known from literature) are reacted with each other using asolvent which does not take part in the reaction, such as dimethylsulfoxide or pyridine, at a temperature between 0° C. and a temperatureat which the solvent refluxes (stage [16]-2), thereby obtaining thecompound represented by formula (AD-3).

[16-1] A preferred aspect of mode [16] is a method in which a compoundrepresented by formula (AD-3) above is manufactured [in formula (AD-3),p, q, R³ and ring A group represented by formula (II) are defined in thesame way as in mode [16] above; R¹ denotes a group arbitrarily selectedfrom among a fluorine atom, a chlorine atom, a bromine atom, a cyanogroup, a methyl group, an ethyl group, an isopropyl group, a tert-butylgroup, a cyclopropyl group, a difluoromethyl group, a trifluoromethylgroup, a 1-hydroxyethyl group, a vinyl group, an acetyl group, a methoxygroup and an ethoxyethyl group; R² denotes a methyl group; and R⁴denotes a group arbitrarily selected from among a fluorine atom, amethyl group and a methoxy group], the manufacturing method includingstages in which a compound represented by formula (AD-3) is obtained[these stages are the same as (stage [16]-1) and (stage [16]-2) in mode[16] above; the definitions of the substituent groups in theintermediates in (stage [16]-1) and (stage [16]-2) are the same as thedefinitions in mode [16-1], and R^(B) in formula (IM-1) is a C₁₋₆ alkylgroup].

[16-2] A more preferred aspect of mode [16] is a method in which acompound represented by formula (AD-3) above is manufactured [in formula(AD-3), p, R¹, R², R⁴ and ring A group represented by formula (II) aredefined in the same way as for mode [16-1] above; q denotes the integer0; and R³ denotes a fluorine atom], the manufacturing method includingstages in which a compound represented by formula (AD-3) is obtained[these stages are the same as (stage [16]-1) and (stage [16]-2) in mode[16] above; the definitions of the substituent groups in theintermediates in (stage [16]-1) and (stage [16]-2) are the same as thedefinitions in mode [16-2], and R^(B) in formula (IM-1) is a C₁₋₆ alkylgroup].

[16-3] A yet more preferred aspect of mode [16] is a method in which acompound represented by formula (AD-3) above is manufactured [in formula(AD-3), p, q, R¹, R², R³ and R⁴ are defined in the same way as for mode[16-2] above; ring A group represented by formula (II) is a thiazol-2-ylgroup or a pyrimidin-4-yl group; and a more specific group obtained bycombining the definitions of p, R¹ and ring A group represented byformula (II) is a 4-(trifluoromethyl)thiazol-2-yl group, a5-fluoro-2-methoxypyrimidin-4-yl group, a 2,5-dimethylpyrimidin-4-ylgroup or a 2-methylpyrimidin-4-yl group], the manufacturing methodincluding stages in which a compound represented by formula (AD-3) isobtained [these stages are the same as (stage [16]-1) and (stage [16]-2)in mode [16] above; the definitions of the substituent groups in theintermediates in (stage [16]-1) and (stage [16]-2) are the same as thedefinitions in mode [16-3], and R^(B) in formula (IM-1) is a C₁₋₆ alkylgroup].

[17] A seventeenth mode of the present invention is a method formanufacturing a compound represented by formula (AD-3) below:

[in formula (AD-3), p denotes an integer between 0 and 3; q denotes aninteger between 0 and 2; R¹ groups each independently denote a grouparbitrarily selected from among a halogen atom, a cyano group, a C₁₋₆alkyl group, a C₃₋₈ cycloalkyl group, a halogenated C₁₋₆ alkyl group, aC₂₋₆ alkenyl group, a C₁₋₆ alkoxy group, a C₁₋₆ alkoxy-C₁₋₆ alkyl group,a hydroxy-C₁₋₆ alkyl group and a C₂₋₇ alkanoyl group; R² denotes a C₁₋₆alkyl group; R³ denotes a group arbitrarily selected from among ahydrogen atom and a fluorine atom; R⁴ groups each independently denote agroup arbitrarily selected from among a halogen atom, a C₁₋₆ alkyl groupand a C₁₋₆ alkoxy group; and ring A group represented by formula (II):

denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarilyselected from among a thiazol-2-yl group, a thiazol-4-yl group, a1-methyl-1H-imidazol-4-yl group, a 1,3,4-thiadiazol-2-yl group, a1,2,4-thiadiazol-5-yl group, a pyridin-2-yl group, a pyridazin-3-ylgroup, a pyrimidin-2-yl group, a pyrimidin-4-yl group and a pyrazin-2-ylgroup], the manufacturing method including a stage in which a compoundrepresented by formula (AD-2):

[in formula (AD-2), p, R¹, R², R and ring A group represented by formula(II) are defined in the same way as for formula (AD-3) in mode [17]] anda compound represented by formula (IM-1):

[in formula (IM-1), q and R are defined in the same way as for formula(AD-3) in mode [17]; and R^(B) denotes a C₁₋₆ alkyl group] or a saltthereof (the compound represented by formula (IM-1) and salt thereof arecommercially available compounds or compounds that can be easilyobtained from commercially available compounds using manufacturingmethods known from literature) are reacted with each other using asolvent which does not take part in the reaction, such as dimethylsulfoxide or pyridine, at a temperature between 0° C. and a temperatureat which the solvent refluxes (stage [17]-1), thereby obtaining thecompound represented by formula (AD-3).

[17-1] A preferred aspect of mode [17] is a method in which a compoundrepresented by formula (AD-3) above is manufactured [in formula (AD-3),p, q, R³ and ring A group represented by formula (II) are defined in thesame way as in mode [17] above; R¹ denotes a group arbitrarily selectedfrom among a fluorine atom, a chlorine atom, a bromine atom, a cyanogroup, a methyl group, an ethyl group, an isopropyl group, a tert-butylgroup, a cyclopropyl group, a difluoromethyl group, a trifluoromethylgroup, a 1-hydroxyethyl group, a vinyl group, an acetyl group, a methoxygroup and an ethoxyethyl group; R² denotes a methyl group; and R⁴denotes a group arbitrarily selected from among a fluorine atom, amethyl group and a methoxy group], the manufacturing method including astage in which a compound represented by formula (AD-3) is obtained[this stage is the same as (stage [17]-1) in mode [17] above; thedefinitions of the substituent groups in the intermediate in (stage[17]-1) are the same as the definitions in mode [17-1], and R^(B) informula (IM-1) is a C₁₋₆ alkyl group].

[17-2] A more preferred aspect of mode [17] is a method in which acompound represented by formula (AD-3) above is manufactured [in formula(AD-3), p, R¹, R², R⁴ and ring A group represented by formula (II) aredefined in the same way as for mode [17-1] above; q denotes the integer0; and R³ denotes a fluorine atom], the manufacturing method including astage in which a compound represented by formula (AD-3) is obtained[this stage is the same as (stage [17]-1) in mode [17] above; thedefinitions of the substituent groups in the intermediate in (stage[17]-1) are the same as the definitions in mode [17-2], and R^(B) informula (IM-1) is a C₁₋₆ alkyl group].

[17-3] A yet more preferred aspect of mode [17] is a method in which acompound represented by formula (AD-3) above is manufactured [in formula(AD-3), p, q, R¹, R², R³ and R⁴ are defined in the same way as for mode[17-2] above; ring A group represented by formula (II) is a thiazol-2-ylgroup or a pyrimidin-4-yl group; and a more specific group obtained bycombining the definitions of p, R¹ and ring A group represented byformula (II) is a 4-(trifluoromethyl)thiazol-2-yl group, a5-fluoro-2-methoxypyrimidin-4-yl group, a 2,5-dimethylpyrimidin-4-ylgroup or a 2-methylpyrimidin-4-yl group], the manufacturing methodincluding a stage in which a compound represented by formula (AD-3) isobtained [this stage is the same as (stage [17]-1) in mode [17] above;the definitions of the substituent groups in the intermediate in (stage[17]-1) are the same as the definitions in mode [17-3], and R^(B) informula (IM-1) is a C₁₋₆ alkyl group].

[18] An eighteenth mode of the present invention is a method formanufacturing a4-heteroaryl-N-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxylicacid amide derivative represented by formula (I) in (Scheme 1) below [in(Scheme 1), p, q, R¹, R², R³, R⁴, R^(B), R^(C), R^(D) and ring A grouprepresented by formula (II) are defined in the same way as modes [1] to[17] above]; and an intermediate for this manufacturing method.

Specific explanations will now be given for the groups in the formulaein modes [1] to [18].

For example, in explanations relating to the compound of the presentinvention, “C₁₋₆” means that the number of constituent carbon atoms isbetween 1 and 6 and, unless explicitly stated otherwise, denotes thenumber of carbon atoms in a straight chain, branched chain or cyclicgroup. The number of constituent carbon atoms includes the total numberof carbon atoms in a group that includes a straight chain or branchedchain group substituted with a cyclic group or in a group that includesa cyclic group substituted with a straight chain or branched chaingroup. Therefore, a chain-like group means “a straight chain or branchedchain having 1 to 6 constituent carbon atoms”. In addition, a cyclicgroup means “a cyclic group in which the number of constituent carbonatoms in the ring is 1 to 6”. A group that includes a chain-like groupand a cyclic group means “a group having a total of 1 to 6 carbonatoms”.

Unless explicitly stated otherwise, the term “halogen atom” in thepresent specification includes, for example, fluorine atoms, chlorineatoms, bromine atoms, iodine atoms, and the like.

Unless explicitly stated otherwise, the term “C₁₋₆ alkyl group” in thepresent specification includes, for example, methylethyl groups, propylgroups, isopropyl groups, butyl groups, isobutyl groups, sec-butylgroups, tert-butyl groups, pentyl groups, isopentyl groups, neopentylgroups, tert-pentyl3-methylbutyl groups, 1,2-dimethylpropyl groups,1-ethylpropyl groups, hexyl groups, isohexyl groups, 1-methylpentylgroups, 2-methylpentyl groups, 3-methylpentyl groups, 1,1-dimethylbutylgroups, 1,2-dimethylbutyl groups, 2,2-dimethylbutyl groups,1,3-dimethylbutyl groups, 2,3-dimethylbutyl groups, 3,3-dimethylbutylgroups, 1-ethylbutyl groups, 2-ethylbutyl groups, 1,1,2-trimethylpropylgroups, 1,2,2-trimethylpropyl groups, 1-ethyl-1-methylpropyl groups,1-ethyl-2-methylpropyl groups, cyclopropyl groups, cyclobutyl groups,cyclopentyl groups, cyclohexyl groups, cyclopropylmethyl groups,cyclobutylmethyl groups, cyclopentylmethyl groups, 1-cyclopropylethylgroups, 2-cyclopropylethyl groups, 2-cyclobutylethyl groups,2-methylcyclopropyl groups, and the like.

Unless explicitly stated otherwise, the term “halogenated” in thepresent specification means that 1 to 5 of the “halogen atoms” mentionedabove may be present as substituent groups. In addition, the term“halogenated” may also be written as “optionally halogenated” or“halogeno”.

Unless explicitly stated otherwise, the term “halogenated C₁₋₆ alkylgroup” in the present specification means a group in which the “C₁₋₆alkyl groups” mentioned above are arbitrarily substituted with 1 to 5halogen atoms, and examples thereof include fluoromethyl groups,difluoromethyl groups, trifluoromethyl groups, 2,2,2-trifluoroethylgroups, 1,1,2,2-tetrafluoroethyl groups and pentafluoroethyl groups.

Unless explicitly stated otherwise, the term “C₃₋₈ cycloalkyl group” inthe present specification includes, for example, cyclopropyl groups,cyclobutyl groups, cyclopentyl groups, cyclohexyl groups, cycloheptylgroups and cyclooctyl groups.

Unless explicitly stated otherwise, the term “C₂₋₆ alkenyl group” in thepresent specification includes, for example, vinyl groups, allyl groups,isopropenyl groups, 1-propen-1-yl groups, 2-methylallyl groups, butenylgroups, pentenyl groups, isopentenyl groups, hexenyl groups,1-cyclopropen-1-yl groups, 2-cyclopropen-1-yl groups, 1-cyclobuten-1-ylgroups, 1-cyclopenten-1-yl groups, 2-cyclopenten-1-yl groups,3-cyclopenten-1-yl groups, 1-cyclohexen-1-yl groups, 2-cyclohexen-1-ylgroups, 3-cyclohexen-1-yl groups, 2,4-cyclopentadien-1-yl groups,2,5-cyclohexadien-1-yl groups, and the like.

Unless explicitly stated otherwise, the term “C₁₋₆ alkoxy group” in thepresent specification includes, for example, methoxy groups, ethoxygroups, propoxy groups, isopropoxy groups, butoxy groups, isobutoxygroups, sec-butoxy groups, tert-butoxy groups, pentyloxy groups,isopentyloxy groups, neopentyloxy groups, tert-pentyloxy groups,1-methylbutoxy groups, 2-methylbutoxy groups, 1,2-dimethylpropoxygroups, 1-ethylpropoxy groups, hexyloxy groups, isohexyloxy groups,1-methylpentyloxy groups, 2-methylpentyloxy groups, 3-methylpentyloxygroups, 1,1-dimethylbutyloxy groups, 1,2-dimethylbutyloxy groups,2,2-dimethylbutyloxy groups, 1,3-dimethylbutyloxy groups,2,3-dimethylbutyloxy groups, 3,3-dimethylbutoxy groups, 1-ethylbutyloxygroups, 2-ethylbutyloxy groups, 1,1,2-trimethylpropyloxy groups,1,2,2-trimethylpropyloxy groups, 1-ethyl-1-methylpropyloxy groups,1-ethyl-2-methylpropyloxy groups, cyclopropyloxy groups, cyclobutyloxygroups, cyclopentyloxy groups, cyclohexyloxy groups, cyclopropylmethoxygroups, cyclobutylmethoxy groups, cyclopentylmethoxy groups,1-cyclopropylethoxy groups, 2-cyclopropylethoxy groups,2-cyclobutylethoxy groups, 2-methylcyclopropyloxy groups, and the like.

Unless explicitly stated otherwise, the term “C₁₋₆ alkoxy-C₁₋₆ alkylgroup” in the present specification means groups in which the “C₁₋₆alkyl groups” mentioned above are substituted with the “C₁₋₆ alkoxygroups” mentioned above. Unless explicitly stated otherwise, the term“C₁₋₆ alkoxy-C₁₋₆ alkyl group” in the present specification includes,for example, methoxymethyl groups, methoxyethyl groups, ethoxymethylgroups, ethoxyethyl groups, 1,1-dimethoxymethyl groups,1,1-diethoxyethyl groups, and the like.

Unless explicitly stated otherwise, the term “hydroxy-C₁₋₆ alkyl group”in the present specification means groups in which the “C₁₋₆ alkylgroups” mentioned above are arbitrarily substituted with 1 to 5 hydroxylgroups, and examples thereof include hydroxymethyl groups, hydroxyethylgroups (specifically, 1-hydroxyethyl groups and 2-hydroxyethyl groups),hydroxypropyl groups (specifically, 1-hydroxypropyl groups,2-hydroxypropyl groups, 3-hydroxypropyl groups, and the like) and2-hydroxy-2-methyl-ethyl groups.

Unless explicitly stated otherwise, the term “C₂₋₇ alkanoyl group” inthe present specification includes, for example, acetyl groups,propionyl groups, butyryl groups, isobutyryl groups, valeryl groups,isovaleryl groups, pivaloyl groups, hexanoyl groups, heptanoyl groups,cyclopropylcarbonyl groups, cyclobutylcarbonyl groups,cyclopentylcarbonyl groups, cyclohexylcarbonyl groups,cyclopropylmethylcarbonyl groups, 2-methylcyclopropylcarbonyl groups,and the like.

Unless explicitly stated otherwise, the term “monocyclic 5- to6-membered heteroaryl group” in the present specification means amonocyclic 5- to 6-membered heteroaryl ring group having 1 to 5heteroatoms selected from among nitrogen atoms, sulfur atoms and oxygenatoms.

Unless explicitly stated otherwise, the term “monocyclic 5- to6-membered heteroaryl group” in the present specification includes, forexample, pyrrolyl groups, furyl groups, thienyl groups, thiazolylgroups, oxazolyl groups, 1H-imidazolyl groups, isothiazolyl groups,isoxazolyl groups, 1H-pyrazolyl groups, 1,2,4-thiadiazolyl groups,1,2,4-oxadiazolyl groups, 1H-1,2,4-triazolyl groups, 1,2,5-thiadiazolylgroups, 1,2,5-oxadiazolyl (furazanyl) groups, 2H-1,2,3-triazolyl groups,1,3,4-thiadiazolyl groups, 1,3,4-oxadiazolyl groups, 4H-1,2,4-triazolylgroups, 1,2,4-thiadiazolyl groups, 1,2,4-oxadiazolyl groups,1H-1,2,4-triazolyl groups, 1,2,3-thiadiazolyl groups, 1,2,3-oxadiazolylgroups, 1H-1,2,3-triazolyl groups, 1,2,3,4-thiatriazolyl groups,1,2,3,4-oxatriazolyl groups, 1,2,3,5-thiatriazolyl groups,1,2,3,5-oxatriazolyl groups, 1H-tetrazolyl groups, 2H-tetrazolyl groups,pyridinyl groups, pyridazinyl groups, pyrimidinyl groups, pyrazinylgroups, 1,2,3-triazinyl groups, 1,2,4-triazinyl groups, 1,3,5-triazinylgroups, 1,2,4,5-tetrazinyl groups, 1,2,3,4-tetrazinyl groups,1,2,3,5-tetrazinyl groups, and the like.

Unless explicitly stated otherwise, the term “C₇₋₂₀ aralkyl group” inthe present specification includes, for example, benzyl groups,phenethyl groups, diphenylmethyl groups, 2,2-diphenylethyl groups,3-phenylpropyl groups, 4-phenylbutyl groups, 5-phenylpentyl groups,2-biphenylmethyl groups, 3-biphenylmethyl groups, 4-biphenylmethylgroups, 1-naphthylmethyl groups, 2-naphthylmethyl groups,2-(1-naphthyl)ethyl groups, 2-(2-naphthyl)ethyl groups, 1-indanylmethylgroups, 2-indanylmethyl groups, 1,2,3,4-tetrahydronaphthalen-1-ylmethylgroups, 1,2,3,4-tetrahydronaphthalen-2-ylmethyl groups, and the like.

Unless explicitly stated otherwise, cases in the present specificationin which a cyclic group is substituted with a variable substituent groupmeans that the variable substituent group does not bond to a specificcarbon atom in the cyclic group or to a specific NH group in the cyclicgroup. For example, variable substituent group R^(x) in formula A belowcan be substituted at any of carbon atoms i, ii, iii, iv or v in formulaA, variable substituent group R^(y) in formula B below can besubstituted at either of carbon atoms vi or vii in formula B, andvariable substituent group R^(z) in formula C below can be substitutedat any of carbon atoms viii, ix, x or xi in formula C.

In all of the modes described above, when the term “compound” is used,this can also mean “a pharmaceutically acceptable salt of the compound”.

Depending on the types of substituent group, a compound of the presentinvention may form an acid addition salt or form a salt with a base.Such salts are not particularly limited as long as these arepharmaceutically acceptable salts, but examples thereof include metalsalts, ammonium salts, salts with organic bases, salts with inorganicbases, salts with organic acids and salts with basic or acidic aminoacids. Preferred examples of metal salts include alkali metal salts suchas lithium salts, sodium salts, potassium salts and cesium salts,alkaline earth metal salts such as calcium salts, magnesium salts andbarium salts, and aluminum salts (these include, for example,mono-salts, disodium salts and dipotassium salts). Preferred examples ofsalts with organic bases include salts with methylamine, ethylamine,t-butylamine, t-octylamine, diethylamine, trimethylamine, triethylamine,cyclohexylamine, dicyclohexylamine, dibenzylamine, ethanolamine,diethanolamine, triethanolamine, piperidine, morpholine, pyridine,picoline, lysine, arginine, ornithine, ethylenediamine,N-methylglucamine, glucosamine, phenylglycine alkyl esters, guanidine,2,6-lutidine, ethanolamine, diethanolamine, triethanolamine,N,N′-dibenzylethylenediamine, and the like. Preferred examples of saltswith inorganic acids include salts with hydrochloric acid, hydrobromicacid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, andthe like. Preferred examples of salts with organic acids include saltswith aliphatic monocarboxylic acids such as formic acid, acetic acid,trifluoroacetic acid, propionic acid, butyric acid, valeric acid,enanthic acid, capric acid, myristic acid, palmitic acid, stearic acid,lactic acid, sorbic acid and mandelic acid, salts with aliphaticdicarboxylic acids such as oxalic acid, malonic acid, succinic acid,fumaric acid, maleic acid, malic acid and tartaric acid, salts withaliphatic tricarboxylic acids such as citric acid, salts with aromaticmonocarboxylic acids such as benzoic acid and salicylic acid, salts witharomatic dicarboxylic acids such as phthalic acid, salts with organiccarboxylic acids such as cinnamic acid, glycolic acid, pyruvic acid,oxylic acid, salicylic acid and N-acetylcysteine, salts with organicsulfonic acids such as methanesulfonic acid, benzenesulfonic acid andp-toluenesulfonic acid, and acid addition salts with acidic amino acidssuch as aspartic acid and glutamic acid. Preferred examples of saltswith basic amino acids include salts with arginine, lysine, ornithine,and the like, and preferred examples of salts with acidic amino acidsinclude salts with aspartic acid, glutamic acid, and the like. Of these,pharmaceutically acceptable salts are preferred. For example, in caseswhere an acidic functional group is present in the compound, aninorganic salt such as an alkali metal salt (for example, a sodium salt,potassium salt, or the like), an alkaline earth metal salt (for example,a calcium salt, magnesium salt, barium salt, or the like), an ammoniumsalt, or the like, can be used, and in cases where a basic functionalgroup is present in the compound, a salt with an inorganic acid such ashydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid orphosphoric acid or a salt with an organic acid such as acetic acid,phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid,citric acid, succinic acid, methanesulfonic acid or p-toluenesulfonicacid can be used.

These salts can be obtained using conventional methods, for example bymixing the compound of the present invention with a solution thatcontains an appropriate quantity of acid or base, thereby forming thetarget salt, and then separating the salt by filtration or distillingoff the mixed solvent. In addition, the compound of the presentinvention or salt thereof can form a solvate with a solvent such aswater, ethanol or glycerol.

“Handbook of Pharmaceutical Salts: Properties, Selection, and Use” Stahl& Wermuth (Wiley-VCH, 2002) has been published as a review relating tosalts, and detailed explanations are available in this publication.These salts can be manufactured by referring to this review.

The compound of the present invention may be present in a non-solvatedform or a solvated form. In the present specification, the term“solvate” means a molecular complex that includes the compound of thepresent invention and one or more pharmaceutically acceptable solventmolecules (for example, water or ethanol). When the solvent molecule iswater, the specific term “hydrate” is used.

In cases where the compound of the present invention has isomers such asgeometric isomers, configuration isomers, tautomeric isomers, opticalisomers, diastereomers, regioisomers or rotational isomers, individualisomers and mixtures thereof are encompassed by the compound of thepresent invention. Furthermore, in cases where optical isomers arepresent in the compound of the present invention, an optical isomer thathas been separated from a racemate of the compound is encompassed by thecompound of the present invention.

In cases where the compound of the present invention has one or moreasymmetric carbon atoms, two or more diastereomers may be present. Inaddition, in cases where the compound of the present invention containsa “C₂₋₆ alkenyl group”, geometric isomers (cis/trans isomers or Z/Eisomers) may be present. In addition, in cases where structural isomerscan be interconverted due to low energy barriers, tautomeric isomerismmay occur. Examples of tautomeric isomerism include proton tautomericisomerism in compounds having imino groups, keto groups or oxime groups.

In cases where the compound of the present invention includes geometricisomers, configuration isomers, diastereomers, conformational isomers,or the like, these may be isolated using publicly known means.

In addition, in cases where the compound of the present invention is anoptically active compound, a racemate may be separated into the (+)isomer or (−) isomer [D isomer or L isomer] using a conventional opticalresolution means.

In cases where the compound of the present invention includes opticalisomers, diastereomers, regioisomers, rotational isomers or tautomericisomers, each isomer can be obtained as a single compound by using apublicly known synthesis means or separation means. Examples of opticalresolution means include publicly known methods such as (1) partitioningrecrystallization methods, (2) diastereomer methods and (3) chiralcolumn methods.

(1) Partitioning recrystallization method: A method in which an opticalresolution agent ionically bonds to a racemate so as to obtaincrystalline diastereomers, these diastereomers are separated by apartitioning recrystallization method and, if necessary, a freeoptically pure compound is obtained by means of a neutralization step.Examples of optical resolution agents include (+)-mandelic acid,(−)-mandelic acid, (+)-tartaric acid, (−)-tartaric acid,(+)-1-phenethylamine, (−)-1-phenethylamine, cinchonine, (−)-cinchonidineand brucine.

(2) Diastereomer method: A method in which an optical resolution agentis covalently bonded (reacted) to a racemate mixture so as to obtain amixture of diastereomers, this mixture of diastereomers is separatedinto optically pure diastereomers by means of a conventional separationmeans (for example, partitioning recrystallization, silica gel columnchromatography or high performance liquid chromatography (HPLC)), and achemical treatment is carried out by means of a hydrolysis reaction orthe like so as to remove the optical resolution agent, thereby obtainingan optically pure optical isomer. For example, in cases where thecompound of the present invention has a hydroxyl group, a primary aminogroup or a secondary amino group in the molecule, a condensationreaction is carried out between the compound and an optically activeorganic acid (for example, MTPA(α-methoxy-α-(trifluoromethyl)phenylacetic acid) or (−)-methoxyaceticacid), thereby obtaining diastereomers of the corresponding ester oramide. Meanwhile, in cases where the compound of the present inventioncontains a carboxyl group, a condensation reaction is carried outbetween the compound and an optically active amine or alcohol reagent,thereby obtaining diastereomers of the corresponding amide or ester. Thethus separated diastereomers are converted into optical isomers of theoriginal compound by carrying out an acid hydrolysis reaction or basehydrolysis reaction.

(3) Chiral column method: A method in which direct optical resolution iscarried out by subjecting a racemate or a salt thereof to chromatographyin a chiral column (a column for separating optical isomers). Forexample, in the case of high performance liquid chromatography (HPLC), amixture of optical isomers is added to a chiral column such as a CHIRALseries column manufactured by Daicel Corporation, and development iscarried out using water, a variety of buffer solutions (for example, aphosphoric acid buffer solution) or organic solvents (for example,ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid ordiethylamine) either individually or as a mixed solution, therebyenabling separation of optical isomers. In addition, in the case of gaschromatography, for example, separation can be carried out using achiral column such as CP-Chirasil-DeX CB (manufactured by GL SciencesInc.).

The compound of the present invention may be crystalline, and thecrystal form thereof may be a single form or a mixture of forms.

The compound of the present invention may be a pharmaceuticallyacceptable cocrystal or cocrystal salt. Here, cocrystal and cocrystalsalt means a crystalline substance constituted from two or more distinctsubstances which are solids at room temperature and which exhibitmutually different physical properties (for example, structure, meltingpoint, heater fusion, hygroscopic properties, solubility, stability, andthe like). The cocrystal or cocrystal salt may be manufactured accordingto a publicly known cocrystallization method.

The compound of the present invention encompasses compounds that arelabeled or substituted with isotopes (for example, hydrogen isotopessuch as ²H and ³H, carbon isotopes such as ¹¹C, ¹³C and ¹⁴C, chlorineisotopes such as ³⁶Cl, fluorine isotopes such as ¹⁸F, iodine isotopessuch as ¹²³I and ¹²⁵I, nitrogen isotopes such as ¹³N and ¹⁵N, oxygenisotopes such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus isotopes such as ³²P, andsulfur isotopes such as ³⁵S).

If labeled or substituted with certain types of isotope (for example,positron-emitting isotopes such as ¹¹C, ¹⁸F, ¹⁵O and ¹³N), the compoundof the present invention can be used as, for example, a tracer (PETtracer) used in positron emission tomography (PET), and is useful infields such as medical diagnostics.

If labeled or substituted with certain types of isotopic label, thecompound of the present invention is useful in tissue distributionresearch for drugs and/or substrates. For example, ³H and ¹⁴C are usefulfor such research purposes due to labeling or substitution being easyand detection means being simple.

If isotopically labeled, the compound of the present invention can beobtained using conventional techniques that are known by persons skilledin the art or by methods similar to the synthesis methods disclosed inthe working examples described below. In addition, obtained isotopicallylabeled compounds can be used instead of unlabeled compounds inpharmacological tests.

[Methods for Manufacturing Compounds Represented by Formula (ET-1),Formula (PY-1) and Formula (PY-2) and Separate Method for ManufacturingCompound Represented by Formula (AD-1) in the Present Invention]

Detailed explanations will now be given of methods for manufacturingcompounds represented by formula (ET-1), formula (PY-1) and formula(PY-2) in (Scheme 2) below and a separate method for manufacturing acompound represented by formula (AD-1) in the present invention. In thepresent invention, compounds represented by formula (ET-1), formula(PY-1), formula (PY-2) and formula (AD-1), salts of these compounds andsolvates of these compounds and salts can be easily manufactured bycombining ordinary known chemical manufacturing methods that use, asstarting materials or synthesis intermediates, commercially availablecompounds or compounds able to be easily obtained from commerciallyavailable compounds using manufacturing methods known from literature,and can be manufactured according to the representative manufacturingmethods shown below. In addition, the present invention is in no waylimited to the manufacturing methods explained below.

Unless explicitly stated otherwise, the definitions of p, R¹, R², R³,R^(B), R^(C), R^(D) and ring A represented by formula (II) in theformulae in the manufacturing methods for compounds represented byformula (ET-1), formula (PY-1), formula (PY-2) and formula (AD-1) arethe same as the definitions described in modes [1] to [18] above. Unlessexplicitly stated otherwise, the definition of R^(A) in themanufacturing methods is a C₁₋₆ alkyl group (for example, a methyl groupor ethyl group), a C₆₋₁₄ aryl group (for example, a phenyl group) or aC₇₋₂₀ aralkyl group (for example, a benzyl group). Unless explicitlystated otherwise, the definition of X in the manufacturing methods is ahalogen atom.

In the manufacturing methods described below, raw material compoundsused in the manufacture of compounds represented by formula (ET-1),formula (PY-1), formula (PY-2) and formula (AD-1) may form salts, andexamples of such salts include salts similar to the salts of formula (I)above. In addition, raw material compounds used in the manufacture ofcompounds represented by formula (ET-1), formula (PY-1), formula (PY-2)and formula (AD-1) may be used in subsequent reactions either asreaction solutions or as purified products, but can be isolated fromreaction mixtures using conventional methods, and can be easily purifiedusing publicly known separation means such as extraction, concentration,neutralization, filtration, distillation, recrystallization orchromatography.

Examples of solvents able to be used in the recrystallization mentionedabove include water; alcohols such as methanol, ethanol, 2-propanol andbutanol; ethers such as diethyl ether, tetrahydrofuran and 1,4-dioxane;hydrocarbons such as n-hexane, cyclohexane and heptane; aromatichydrocarbons such as benzene, toluene and xylene; amides such asN,N-dimethylformamide, N,N-dimethylacetamide and1,3-dimethyl-2-imidazolidinone; halogenated hydrocarbons such aschloroform, methylene chloride and 1,2-dichloroethane; nitriles such asacetonitrile; ketones such as acetone and diphenyl ketone; esters suchas methyl acetate and ethyl acetate; sulfoxides such as dimethylsulfoxide; and organic acids such as acetic acid, trifluoroacetic acid,methanesulfonic acid and p-toluenesulfonic acid. It is possible to useone of these solvents in isolation or a mixture of two or more typesthereof at appropriate proportions, such as 1:1 to 1:10. In addition, incases where the compounds in the formulae are commercially available, itis possible to use commercially available compounds without furthermodification or use compounds manufactured using publicly known methodsor methods based on such publicly known methods.

In cases where substituent groups present in compounds represented byformula (ET-1), formula (PY-1), formula (PY-2) and formula (AD-1)contain variable functional groups (for example, carboxyl groups, aminogroups, hydroxyl groups, carbonyl groups, mercapto groups, C₁₋₆alkoxycarbonyl groups, C₆₋₁₄ aryloxycarbonyl groups, C₇₋₂₀aralkyloxycarbonyl groups, sulfo groups (—SO₂OH), halogen atoms, and thelike), a variety of compounds can be manufactured by converting thesefunctional groups using publicly known methods or methods based on suchpublicly known methods.

A “carboxyl group” can be converted by means of a reaction such asesterification, chemical reduction, amidation, or conversion into anoptionally protected amino group.

An “amino group” can be converted by means of a reaction such asamidation, sulfonylation, nitrosation, alkylation, arylation orimidation.

A “hydroxyl group” can be converted by means of a reaction such asesterification, carbamoylation, sulfonylation, alkylation, arylation,oxidation or halogenation.

A “carbonyl group” can be converted by means of a reaction such aschemical reduction, oxidation, imination (including oximation andhydrazonation), (thio)ketalation, alkylidenation andthiocarbonylationation.

A “mercapto (—SH) group” can be converted by means of a reaction such asalkylation or oxidation.

A “C₁₋₆ alkoxycarbonyl group”, “C₆₋₁₄ aryloxycarbonyl group” or “C₇₋₂₀aralkyloxycarbonyl group” can be converted by means of a reaction suchas chemical reduction or hydrolysis.

A “sulfo (—SO₂OH) group” can be converted by means of a reaction such assulfonamidation or chemical reduction.

A “halogen atom” can be converted by means of, for example, a variety ofnucleophilic substitution reactions, a variety of coupling reactions,and the like.

In cases where a compound is obtained in a free form in the reactionsmentioned above, the compound may be converted into a salt using aconventional method, and in cases where a compound is obtained in theform of a salt, the salt may be converted into a free compound oranother salt using a conventional method.

These functional groups may be converted according to methods disclosedin, for example, Richard C. Larock et al., “Comprehensive OrganicTransformations”, second edition, October 1999 (Wiley-VCH).

In addition, in the reactions in the methods for manufacturing compoundsrepresented by formula (ET-1), formula (PY-1), formula (PY-2) andformula (AD-1) and the reactions used to synthesize the raw materialcompounds in the present invention, in cases where a reactive group suchas a hydroxyl group (an alcoholic hydroxyl group, phenolic hydroxylgroup, heterocyclic hydroxyl group, or the like), an amino group, acarboxyl group or a thiol group is present as a substituent group, it ispossible to protect these groups as appropriate in the reaction stepsand remove the protecting groups at an appropriate stage.

Examples of protecting groups able to be used for these hydroxyl groups(alcoholic hydroxyl groups, phenolic hydroxyl groups, heterocyclichydroxyl groups, and the like), include C₁₋₆ alkyl groups such as methylgroups, ethyl groups, n-propyl groups, isopropyl groups, n-butyl groupsand tert-butyl groups; alkoxyalkyl groups such as methoxymethyl (MOM)groups and methoxyethoxymethyl (MEM) groups; tetrahydropyranyl (THP)groups; C₇₋₂₀ aralkyl groups such as benzyl (Bn) groups andtriphenylmethyl (Tr) groups; silyl groups such as trimethylsilyl (TMS)groups, triethylsilyl (TES) groups, t-butyldimethylsilyl (TBDMS) groupsand t-butyldiphenylsilyl (TBDPS) groups; alkanoyl groups such as acetyl(Ac) groups, ethylcarbonyl groups and pivaloyl (Piv) groups; C₇₋₂₀aralkylcarbonyl groups such as benzylcarbonyl groups; aroyl groups suchas benzoyl (Bz) groups; alkoxycarbonyl groups such as methoxycarbonylgroups, ethoxycarbonyl groups and t-butoxycarbonyl (Boc) groups; andC₇₋₂₀ aralkyloxycarbonyl groups such as benzyloxycarbonyl (Z) groups.

Examples of protecting groups able to be used for these amino groups(—NH₂ groups) or imino groups (—NH— groups) include alkanoyl groups suchas acetyl (Ac) groups, ethylcarbonyl groups and pivaloyl (Piv) groups;alkoxycarbonyl groups such as methoxycarbonyl groups, ethoxycarbonylgroups and t-butoxycarbonyl (Boc) groups; allyloxycarbonyl (Alloc)groups; fluorenylmethoxycarbonyl (Fmoc) groups; phenyloxycarbonylgroups; C₇₋₂₀ aralkyloxycarbonyl groups such as benzyloxycarbonyl (Z)groups, para-methoxybenzyloxycarbonyl groups andpara-nitrobenzoyloxycarbonyl groups; C₇₋₂₀ aralkyl groups such as benzyl(Bn) groups and triphenylmethyl (Tr) groups; aroyl groups such asbenzoyl (Bz) groups; C₇₋₂₀ aralkylcarbonyl groups such as benzylcarbonylgroups; sulfonyl groups such as methanesulfonyl (Ms) groups,p-toluenesulfonyl (Ts) groups, 2,4-dinitrobenzenesulfonyl (Nos) groupsand benzenesulfonyl (Bs) groups; 2-(trimethylsilyl)ethoxymethyl (SEM)groups; phthaloyl (Pht) groups; and N,N-dimethylaminomethylene groups.

Examples of protecting groups able to be used for these carboxyl groups(—COOH groups) include alkyl groups such as methyl groups, ethyl groups,n-propyl groups, isopropyl groups, n-butyl groups and tert-butyl groups;alkenyl groups such as allyl groups; aryl groups such as phenyl (Ph)groups; C₇₋₂₀ aralkyl groups such as benzyl (Bn) groups andtriphenylmethyl (Tr) groups; and silyl groups such as trimethylsilyl(TMS) groups, triethylsilyl (TES) groups, t-butyldimethylsilyl (TBDMS)groups and t-butyldiphenylsilyl (TBDPS) groups.

Examples of protecting groups able to be used for these thiol groups(—SH groups) include alkyl groups such as methyl groups, ethyl groups,n-propyl groups, isopropyl groups, n-butyl groups and tert-butyl groups;C₇₋₂₀ aralkyl groups such as benzyl (Bn) groups and triphenylmethyl (Tr)groups; alkanoyl groups such as acetyl (Ac) groups, ethylcarbonyl groupsand pivaloyl (Piv) groups; and aroyl groups such as benzoyl (Bz) groups.

Methods for introducing and removing such protecting groups are carriedout as appropriate according to the type of group to be protected andthe type of protecting group, but it is possible to use, for example, amethod disclosed in Greene et al., “Protective Groups in OrganicSynthesis”, fourth edition, 2007 (John Wiley & Sons).

As a method for deprotecting a protecting group, it is possible tohydrolyze and deprotect acyl type protecting groups, for examplealkanoyl groups such as acetyl (Ac) groups, ethylcarbonyl groups andpivaloyl (Piv) groups; alkoxycarbonyl groups such as methoxycarbonylgroups, ethoxycarbonyl groups and t-butoxycarbonyl (Boc) groups; andaroyl groups such as benzoyl (Bz) groups, using, for example, anappropriate base such as an alkali metal hydroxide, such as lithiumhydroxide, sodium hydroxide or potassium hydroxide.

Alkoxyalkyl protecting groups such as methoxymethyl (MOM) groups,methoxyethoxymethyl (MEM) groups and tetrahydropyranyl (THP) groups;alkoxycarbonyl protecting groups such as t-butoxycarbonyl (Boc) groups;C₇₋₂₀ aralkyloxycarbonyl protecting groups such as benzyloxycarbonyl (Z)groups and para-methoxybenzyloxycarbonyl groups; and silyl protectinggroups such as trimethylsilyl (TMS) groups, triethylsilyl (TES) groupsand t-butyldimethylsilyl (TBDMS) groups can be deprotected using anappropriate acid such as acetic acid, hydrochloric acid, hydrobromicacid, sulfuric acid, phosphoric acid, trifluoroacetic acid ortrifluoromethanesulfonic acid, or a combination of these acids.

In addition, these silyl protecting groups can be deprotected using anappropriate reagent that generates fluoride ions (F), for example areagent such as tetrabutyl ammonium fluoride or hydrogen fluoride.

C₇₋₂₀ aralkyloxycarbonyl groups such as benzyloxycarbonyl (Z) groups,para-methoxybenzyloxycarbonyl groups and para-nitrobenzoyloxycarbonylgroups and C₇₋₂₀ aralkyl groups such as benzyl (Bn) groups can bedeprotected by means of, for example, hydrogenolysis using apalladium-carbon (Pd—C) catalyst.

In addition, benzyl groups can also be deprotected by, for example,Birch reduction in liquid ammonia using metallic sodium.

Triphenylmethyl (Tr) groups can be deprotected using an appropriate acidsuch as acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid,phosphoric acid, trifluoroacetic acid or trifluoromethanesulfonic acid,or a combination of these acids. In addition, triphenylmethyl (Tr)groups can be deprotected by Birch reduction in liquid ammonia usingmetallic sodium or metallic lithium or by hydrogenolysis using apalladium-carbon catalyst.

Sulfonyl (—SO₂—) groups can be deprotected by, for example, one-electronreduction at a low temperature using Na/anthracene or Na/naphthalene, orBirch reduction in liquid ammonia using metallic sodium or metalliclithium.

In addition, among sulfonyl groups, 2-nitrobenzenesulfonyl (Ns) groupscan be deprotected under mild conditions by, for example, reacting witha thiol in the presence of a basic reagent such as potassium carbonateor triethylamine.

These methods for deprotecting protecting groups are merely examples,and deprotection can be carried out using, for example, a methoddisclosed in Greene et al., “Protective Groups in Organic Synthesis”,fourth edition, 2007 (John Wiley & Sons) or using articles that havebeen publicly expressed.

Unless explicitly stated otherwise, reaction conditions in the methodsfor manufacturing compounds represented by formula (ET-1), formula(PY-1), formula (PY-2) and formula (AD-1) described below are asfollows. The reaction temperature is not limited as long as thistemperature falls within the range between −78° C. and the temperatureat which the solvent refluxes. The reaction duration is not limited aslong as this duration is sufficient for the reaction to progressadequately.

With respect to the reaction temperature in the manufacturing methodsdisclosed in the present specification, unless explicitly statedotherwise, the expression “at a temperature between 0° C. and atemperature at which the solvent refluxes” means a temperature within arange between 0° C. and the temperature at which the solvent (or mixedsolvent) used in the reaction refluxes. For example, in cases wheremethanol is used as the solvent, “at a temperature between 0° C. and atemperature at which the solvent refluxes” means a temperature within arange between 0° C. and the temperature at which methanol refluxes.Similarly, the expression “at a temperature between 0° C. and atemperature at which the reaction solution refluxes” means a temperaturewithin a range between 0° C. and a temperature at which the reactionsolution refluxes.

In addition, the steps in the methods for manufacturing compoundsrepresented by formula (ET-1), formula (PY-1), formula (PY-2) andformula (AD-1) may be carried out in the absence of a solvent or bydissolving or suspending raw material compounds prior to the reaction inan appropriate solvent which does not take part in the reaction.Specific examples of solvents that do not take part in the reactioninclude water; saturated hydrocarbon-based solvents such as cyclohexaneand hexane; aromatic hydrocarbon-based solvents such as benzene,chlorobenzene, toluene and xylene; alcoholic solvents such as methanol,ethanol, 1-propanol, 2-propanol, tert-butyl alcohol and2-methoxyethanol; polar amide-based solvents such asN,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphorictriamide and 1,3-dimethyl-2-imidazolidinone; sulfoxide-based solventssuch as dimethyl sulfoxide; nitrile-based solvents such as acetonitrileand propionitrile; ether-based solvents such as diethyl ether,diisopropyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane and1,2-dimethoxyethane; ester-based solvents such as methyl acetate, ethylacetate and butyl acetate; ketone-based solvents such as acetone andmethyl ethyl ketone; halogenated hydrocarbon-based solvents such asdichloromethane, chloroform, carbon tetrachloride and1,2-dichloroethane; basic solvents such as triethylamine,N,N-diisopropylethylamine, pyridine and lutidine; acid anhydrides suchas acetic anhydride; organic acids such as formic acid, acetic acid,propionic acid, trifluoroacetic acid and methanesulfonic acid; andinorganic acids such as hydrochloric acid and sulfuric acid. It ispossible to use one of these solvents in isolation or a mixture ofappropriate proportions of two or more of these solvents, selectedaccording to reaction conditions. Unless explicitly stated otherwise,the term “a solvent which does not take part in the reaction” in themanufacturing method in the present specification means that it ispossible to use a single type of solvent in isolation or use a mixtureof appropriate proportions of two or more solvents, selected accordingto reaction conditions.

Specific examples of bases (or deoxidizing agents) able to be used inthe methods for manufacturing compounds represented by formula (ET-1),formula (PY-1), formula (PY-2) and formula (AD-1) include inorganicbases such as lithium hydroxide, sodium hydroxide, potassium hydroxide,magnesium hydroxide, lithium carbonate, sodium carbonate, potassiumcarbonate, cesium carbonate, calcium carbonate and sodium hydrogencarbonate; organic bases such as triethylamine,N,N-diisopropylethylamine, tributylamine, cyclohexyldimethylamine,pyridine, lutidine, 4-dimethylaminopyridine (DMAP), N,N-dimethylaniline,N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine,1,5-diazabicyclo[4.3.0]-5-nonene, 1,4-diazabicyclo[2.2.2]octane,1,8-diazabicyclo[5.4.0]-7-undecene and imidazole; metal alkoxides suchas sodium methoxide, sodium ethoxide, potassium tert-butoxide and sodiumtert-butoxide; alkali metal hydroxides such as sodium hydroxide andpotassium hydroxide; metal amides such as sodium amide, lithiumdiisopropylamide and lithium hexamethyldisilazide; and organic lithiumreagents such as methyl lithium, n-butyl lithium, sec-butyl lithium andtert-butyl lithium. In addition, specific examples of acids and acidcatalysts able to be used in the method for manufacturing the compoundof the present invention include inorganic acids such as hydrochloricacid, sulfuric acid, nitric acid, hydrobromic acid and phosphoric acid;organic acids such as acetic acid, trifluoroacetic acid, oxalic acid,phthalic acid, fumaric acid, tartaric acid, maleic acid, citric acid,succinic acid, methanesulfonic acid, p-toluenesulfonic acid and10-camphorsulfonic acid; and Lewis acids such as boron trifluoride ethercomplexes, zinc iodide, anhydrous aluminum chloride, anhydrous zincchloride and anhydrous iron chloride. However, acids and acid catalystsable to be used in the method for manufacturing the compound of thepresent invention are not necessarily limited to those listed above.

Salts represented by formula (ET-1), formula (PY-1), formula (PY-2) andformula (AD-1) can be manufactured using publicly known means, forexample, in cases where compounds represented by formula (ET-1), formula(PY-1) and formula (PY-2) are basic compounds, it is possible tomanufacture the salts mentioned above by adding an inorganic acid (amineral acid) such as hydrochloric acid, hydrobromic acid, nitric acid,sulfuric acid or phosphoric acid or an organic acid such as formic acid,acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalicacid, tartaric acid, maleic acid, citric acid, succinic acid, malicacid, methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonicacid, and in cases where compounds represented by formula (CA-1),formula (PY-1) and formula (PY-2) are acidic compounds, it is possibleto manufacture the salts mentioned above by adding an organic base suchas ammonia, trimethylamine, triethylamine, pyridine, picoline,2,6-lutidine, ethanolamine, diethanolamine, triethanolamine,cyclohexylamine, dicyclohexylamine, N,N-diisopropylethylamine,N,N′-dibenzylethylenediamine or a N,N-dialkylaniline or an inorganicbase such as lithium carbonate, sodium carbonate, potassium carbonate,cesium carbonate, lithium hydroxide, sodium hydroxide, potassiumhydroxide or sodium hydrogen carbonate.

<Manufacturing Method A>

Method for manufacturing ester derivative represented by formula (ET-1):

<Step 1>

<W=Boronic Acid Ester>

A boronic acid ester represented by formula (A-2) can be manufacturedusing a method known from literature, for example, according to themethod disclosed in “The Journal of Organic Chemistry”, 60, 7508-2665,1995, by subjecting a compound represented by formula (A-1) to areaction in the presence of a diboron ester such as bis(pinacolato)diboron or bis(neopentyl glycolato) diboron, in the presence of apalladium catalyst such as palladium (II) acetate, palladiumtetrakis(triphenylphosphine), dipalladium tri(dibenzylideneacetone),[1,1′-bis(diphenylphosphino) ferrocene]dichloro palladium (II) or a[1,1′-bis(diphenylphosphino)ferrocene]dichloro palladium(II)-dichloromethane complex, in the presence or absence of aphosphine-based reagent such as triphenylphosphine,tri(tert-butyl)phosphine, tri(o-tolyl)phosphine or2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl and an organic orinorganic base such as triethylamine, N,N-diisopropylethylamine,potassium carbonate or potassium acetate or in the presence or absenceof tetramethyl ammonium chloride, tetrabutyl ammonium chloride or thelike instead of a phosphine-based reagent, in a solvent which does nottake part in the reaction, such as toluene, N,N-dimethylformamide,dimethyl sulfoxide or 1,4-dioxane, or a mixture of these solvents, at atemperature between 0° C. and a temperature at which the solventrefluxes.

<W=Boronic Acid>

A boronic acid represented by formula (A-2) can be manufactured using amethod known from literature, for example, according to the methoddisclosed in “Chemische Berichte” 42, 3090, 1909, by using a solventwhich does not take part in the reaction, such as toluene,tetrahydrofuran or 1,4-dioxane, or a mixture of these solvents, in thepresence of a Grignard reagent such as an alkyl lithium compound, suchas n-butyl lithium or sec-butyl lithium, or isopropyl magnesium chlorideor in the presence of metallic magnesium, adding a trialkyl borate suchas trimethyl borate or triisopropyl borate, subjecting a compoundrepresented by formula (A-1) to a reaction at a temperature between −78°C. and room temperature, then adding an acid such as hydrochloric acidor sulfuric acid, and carrying out a reaction at a temperature between0° C. and a temperature at which the solvent refluxes.

<W=Trifluoroborate Salt>

A trifluoroborate salt represented by formula (A-2) can be manufacturedusing a method known from literature, for example, according to themethod disclosed in “Chemical Reviews”, 108, 288-325, 2008, bysubjecting the boronic acid ester or boronic acid represented by formula(A-2), which are obtained in the methods mentioned above, to a reactionin the presence of potassium hydrogen difluoride (KHF₂) using a solventwhich does not take part in the reaction, such as methanol, ethanol orwater, or a mixture of these solvents, at a temperature between 0° C.and a temperature at which the solvent refluxes.

<W=Boronic Acid N-Methyliminodiacetic Acid (MIDA) Ester>

A boronic acid N-methyliminodiacetic acid (MIDA) ester represented byformula (A-2) can be manufactured using a method known from literature,for example, according to the method disclosed in “The Journal ofOrganometallic Chemistry”, 307 (1), pages 1-6, 1986, by subjecting theboronic acid represented by formula (A-2), which is obtained in themethod mentioned above, to a reaction in the presence ofN-methyliminodiacetic acid (MIDA), using a solvent which does not takepart in the reaction, such as benzene, toluene, xylene or dimethylsulfoxide, or a mixture of these solvents, at a temperature between 0°C. and a temperature at which the solvent refluxes.

<Step 2>

A compound represented by formula (ET-1) can be manufactured using amethod known from literature, for example, according to “The FifthSeries of Experimental Chemistry, 18. Organic Compound SynthesisVI—Organic Synthesis Using Metals—”, pages 327-352, 2004, Maruzen and“Journal of Medicinal Chemistry” 48(20), pages 6326-6339, 2005, bysubjecting a compound represented by formula (A-2), which was obtainedin <Step 1> in <Manufacturing Method A>, and a halogenated heteroarylderivative represented by formula (A-3) to a reaction in the presence ofa palladium catalyst such as palladium (II) acetate (Pd(OAc)₂),palladium tetrakis(triphenylphosphine) (Pd(PPh₃)₄), dipalladiumtri(dibenzylideneacetone) ((dba)₃Pd₂), palladiumbis(dibenzylideneacetone) ((dba)₂Pd) or [1,1′-bis(diphenylphosphino)ferrocene]dichloro palladium (II) (Pd(dppf)Cl₂), a phosphine-basedreagent such as triphenylphosphine, tri(tert-butyl)phosphine,tri(o-tolyl)phosphine, 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenylor 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl and an organicor inorganic base such as triethylamine, N,N-diisopropylethylamine,potassium phosphate, potassium carbonate or cesium carbonate, using asolvent which does not take part in the reaction, such as toluene,xylene, N,N-dimethylformamide, N,N-dimethylacetamide,1,2-dimethoxyethane, acetonitrile (acetonitrile/water), 1,4-dioxane(1,4-dioxane/water) or tetrahydrofuran (tetrahydrofuran/water), or amixture of these solvents, at a temperature between 0° C. and atemperature at which the solvent refluxes. In addition, a compoundrepresented by formula (ET-1) can be manufactured using a similarmethod, using tetramethyl ammonium chloride, tetrabutyl ammoniumchloride, or the like, instead of the phosphine-based reagent.

<Manufacturing Method B>

Method for manufacturing pyridine acid derivative represented by formula(PY-1) (formula (PY-1-1) in cases where R³ is a fluorine atom):

<Step 1>

A compound represented by formula (B-2) can be manufactured according toa method known from literature, for example, a method disclosed in“Bioorganic & Medicinal Chemistry Letters”, 22(10), pages 3431-3436,2012 or “Step (A) in Example 56 on page 116 of WO 2011/073845”(published 23 Jun. 2011), by adding a compound represented by formula(B-1) (in cases where R³ is a fluorine atom, the starting material is2,5-difluoropyridine [CAS No.: 84476-99-3]) at a temperature of −78° C.to a mixed solution of lithium diisopropylamide (LDA) prepared fromN,N-diisopropylamine and n-butyl lithium (an n-hexane solution) in asolvent that is inert in the reaction, such as tetrahydrofuran, diethylether or 1,2-dimethoxyethane, or a mixture of these solvents, stirringfor 3 hours, further adding iodine, and carrying out a reaction at atemperature between −78° C. and 0° C.

<Step 2>

A compound represented by formula (PY-1) can be manufactured accordingto a method known from literature, for example, a method disclosed in“Synthesis”, 12, pages 905-908, 1989, by subjecting the compoundrepresented by formula (B-2), which was obtained in <Step 1> in<Manufacturing Method B> to a sealed tube reaction at a temperaturebetween 0° C. and 150° C. in the presence of aqueous ammonia using asolvent that is inert in the reaction, such as 1,4-dioxane.

<Manufacturing Method C>

Method for manufacturing pyridine acid derivative represented by formula(PY-2):

[In cases where R³ is F, the starting material is2-bromo-5-fluoropyridine [CAS No.: 41404-58-4], which is represented byformula (C-1). In cases where R³ is H, the starting material is2-amino-isonicotinic acid ethyl ester [CAS No.: 13362-30-6], which isrepresented by formula (C-4).]

<Step 1>

According to a method known from literature, for example, a methoddisclosed in WO 2008/126899 (published on 23 Oct. 2008), n-butyl lithium(an n-hexane solution) is added at a temperature of −70° C. to a solventthat is inert in the reaction, such as tetrahydrofuran, diethyl ether or1,2-dimethoxyethane, or a mixture of these solvents. A compoundrepresented by formula (C-2) can be manufactured by adding a compoundrepresented by formula (C-1) dropwise to a mixed solution of n-butyllithium at the same temperature, stirring for 2 hours at thistemperature, adding an excess of dry ice, and carrying out a reaction ata temperature between −70° C. and 0° C.

<Step 2>

A compound represented by formula (C-3) can be manufactured according toa method known from literature, for example, a method disclosed in WO1998/024782 (published on 11 Jun. 1998) by subjecting the compoundrepresented by formula (C-2), which was obtained in <Step 1> in<Manufacturing Method C>, to a sealed tube reaction at a temperaturebetween 0° C. and 150° C. in the presence of a copper catalyst such ascopper iodide using 28% aqueous ammonia and, following the reaction,adding concentrated hydrochloric acid to the reaction solution at atemperature below freezing point.

<Step 3>

A compound represented by formula (C-4) can be manufactured according toa method known from literature, for example, a method disclosed in “TheFourth Series of Experimental Chemistry”, 22, Organic Synthesis IV,Acids, Amino acids and Peptides, pages 1-82, 1992, Maruzen, bysubjecting the compound represented by formula (C-3), which was obtainedin <Step 2> in <Manufacturing Method C>, to a reaction in the presenceof an acidic reagent such as hydrochloric acid, sulfuric acid, thionylchloride or acetyl chloride, using ethanol, at a temperature between 0°C. and a temperature at which the solvent refluxes.

In addition, a compound represented by formula (C-4) can be manufacturedaccording to a method known from literature, for example, a methoddisclosed in “Synthetic Communications”, 31(14), pages 2177-2183, 2001,by subjecting the compound represented by formula (C-3), which wasobtained in <Step 2> in <Manufacturing Method C>, to a reaction in thepresence of ethyl iodide and in the presence of a base such as potassiumcarbonate, sodium carbonate, potassium hydroxide or sodium hydroxide,using a polar solvent, such as N,N-dimethylformamide or dimethylsulfoxide, at a temperature between 0° C. and a temperature at which thesolvent refluxes.

In addition, a compound represented by formula (C-4) can be manufacturedaccording to a method known from literature, for example, a methoddisclosed in “The Fourth Series of Experimental Chemistry”, 22, OrganicSynthesis IV, Acids, Amino acids and Peptides, pages 191-309, 1992,Maruzen, by subjecting the compound represented by formula (C-3), whichwas obtained in <Step 2> in <Manufacturing Method C>, and ethanol to areaction in the presence of a condensing agent, such as1,3-dicyclohexylcarbodiimide (DCC),1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (WSC.HCl),1-hydroxybenzotriazole (Hobt),benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate(a BOP reagent), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl),2-chloro-1,3-dimethylimidazolinium hexafluorophosphate (CIP),4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride(DMTMM), polyphosphoric acid (PPA) or2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate methanaminium (HATU), in a solvent which does nottake part in the reaction, for example a halogen-based solvent such asdichloromethane or chloroform, an ether-based solvent such as diethylether or tetrahydrofuran, aromatic hydrocarbon-based solvent such astoluene or benzene, or a polar solvent such as N,N-dimethylformamide, ata temperature between 0° C. and a temperature at which the solventrefluxes, in the presence or absence of a base such as triethylamine orpyridine.

In addition, a compound represented by formula (C-4) can be similarlymanufactured according to a method known from literature, for example, amethod disclosed in “The Journal of the American Chemical Society”,109(24), pages 7488-7494, 1987, by subjecting the compound representedby formula (C-3) to a reaction in the presence or absence of a base suchas triethylamine, N,N-diisopropylethylamine orN,N-dimethylaminopyridine, using a halogenating agent, such as thionylchloride, oxalyl chloride, phosphoryl chloride, sulfuryl chloride,phosphorus trichloride, phosphorus pentachloride or phosphorustribromide, and a solvent that is inert in the reaction, such as1,4-dioxane, tetrahydrofuran, benzene, toluene, dichloromethane,1,2-dichloroethane or chloroform, or a mixture of these solvents, at atemperature between 0° C. and a temperature at which the solventrefluxes, so as to convert into an acid halide, and then, according to amethod known from literature, for example, a method disclosed in “TheFourth Series of Experimental Chemistry”, 22, Organic Synthesis IV,Acids, Amino acids and Peptides, pages 144-146, 1992, Maruzen, carryingout a reaction using ethanol in the presence of a base such astriethylamine, N,N-diisopropylethylamine, pyridine or4-dimethylaminopyridine, using a solvent which does not take part in thereaction, for example, a halogen-based solvent such as dichloromethane,chloroform or 1,2-dichloro ethane, an ether-based solvent such asdiethyl ether, tetrahydrofuran or 1,4-dioxane, an aromatichydrocarbon-based solvent such as toluene or benzene or a polar solventsuch as N,N-dimethylformamide, at a temperature between 0° C. and atemperature at which the solvent refluxes.

<Step 4>

Using the compound represented by formula (C-4), which was obtained in<Step 3> in <Manufacturing Method C>, a compound represented by formula(C-5) can be manufactured according to a method known from literature,for example, a method disclosed in “Protective Groups in OrganicSynthesis”, 4th Edition, 2007 (John Wiley & Sons), Greene et al., bysubjecting a variety of reagents (for example, methyl chloroformate orthe like in cases where R^(C) is a methyl group; ethyl chloroformate orthe like in cases where R^(C) is an ethyl group; di-tert-butyldicarbonate, 2-(2-tert-butoxycarbonyloxyimino)-2-phenylacetonitrile, orthe like in cases where R^(C) is a tert-butyl group; benzylchloroformate or the like in cases where R^(C) is a benzyl group) to areaction using a method that depends on the type of protecting group(RCOC(═O)—).

<Step 5>

A compound represented by formula (C-6) can be manufactured bysubjecting the compound represented by formula (C-5), which was obtainedin <Step 4> in <Manufacturing Method C>, to a reaction according to<Step 1> in <Manufacturing Method D>, which is described below.

<Step 6>

Using the compound represented by formula (C-6), which was obtained in<Step 5> in <Manufacturing Method C>, a compound represented by formula(C-7) can be manufactured according to a method known from literature,for example, a method disclosed in “Strategic Applications of NamedReactions in Organic Synthesis”, Elsevier Academic Press, 2005, pages116, 117, Curtius Rearrangement, by subjecting diphenylphosphoryl azide(DPPA) to a reaction in the presence of a base such as triethylamine,using a solvent that is inert in the reaction, such as toluene orbenzene, or a mixture of these solvents, at a temperature between 0° C.and a temperature at which the solvent refluxes, and then reacting withtert-butyl alcohol.

<Step 7>

Using the compound represented by formula (C-7), which was obtained in<Step 6> in <Manufacturing Method C>, a compound represented by formula(PY-2) can be manufactured according to a method known from literature,for example, a method disclosed in “Protective Groups in OrganicSynthesis”, 4th Edition, 2007 (John Wiley & Sons), Greene et al., bydeprotecting the protecting group (^(t)BuOC(═O)—).

<Manufacturing Method D>

Method for manufacturing amide derivative represented by formula (AD-1):

<Step 1>

<R^(D)═C₁₋₆ Alkyl Group (for Example, Methyl Group, Ethyl Group, or theLike)>

A compound represented by formula (CA-1) can be manufactured accordingto a method known from literature, for example, a method disclosed in“The Fourth Series of Experimental Chemistry”, 22, Organic Synthesis IV,Acids, Amino acids and Peptides, pages 1-43, 1992, Maruzen, bysubjecting the compound represented by formula (ET-1), which wasobtained in <Step 2> in <Manufacturing Method A>, to a reaction in thepresence of a base, such as lithium hydroxide, sodium hydroxide,potassium hydroxide, lithium carbonate, sodium carbonate or potassiumcarbonate, using water and a solvent that is inert in the reaction, suchas methanol, ethanol, 2-propanol, N,N-dimethylformamide, 1,4-dioxane ortetrahydrofuran, or a mixture of these solvents, at a temperaturebetween 0° C. and a temperature at which the solvent refluxes.

<R^(D)=Tert-Butyl Group>

A compound represented by formula (CA-1) can be manufactured using amethod known from literature, for example, according to a deprotectionmethod disclosed in “Protective Groups in Organic Synthesis”, 4thEdition, 2007 (John Wiley & Sons), Greene et al., by subjecting thecompound represented by formula (ET-1), which was obtained in <Step 2>in <Manufacturing Method A>, to a reaction using an acid, such ashydrochloric acid, sulfuric acid, acetic acid or trifluoroacetic acid,at a temperature between 0° C. and a temperature at which the solventrefluxes.

<R^(D)=Benzyl Group>

A compound represented by formula (CA-1) can be manufactured accordingto a method known from literature, for example, a method disclosed in“The Fourth Series of Experimental Chemistry”, 26, Organic SynthesisVIII, Asymmetric Synthesis, Chemical Reduction, Sugar and LabeledCompounds, pages 159-266, 1992, Maruzen”, by subjecting the compoundrepresented by formula (ET-1), which was obtained in <Step 2> in<Manufacturing Method A>, to a reaction in the presence of a catalyst,such as palladium-carbon (Pd—C), Raney-nickel (Raney-Ni), platinum oxide(PtO₂) or dichlorotri(triphenylphosphine) ruthenium, in a hydrogen gasatmosphere, using a solvent which does not take part in the reaction,for example, an alcoholic solvent such as methanol, ethanol or2-propanol, an ether-based solvent such as diethyl ether,tetrahydrofuran, 1,2-dimethoxyethane or 1,4-dioxane or a polar solventsuch as ethyl acetate or methyl acetate, or a mixture of these solvents,at a temperature between 0° C. and a temperature at which the solventrefluxes.

<Step 2>

Using the compound represented by formula (CA-1), which was obtained in<Step 1> in <Manufacturing Method D>, an active ester is formedaccording to a method known from literature, for example, a methoddisclosed in “Synthesis”, (12), pages 954, 955, 1979, by subjecting acompound represented by ClCOOR^(A) or di-tert-butyl dicarbonate (Boc₂O)to a reaction in the presence of a base, such asN,N-diisopropylethylamine, triethylamine or pyridine, using a solventwhich does not take part in the reaction, such as tetrahydrofuran,diethyl ether or 1,2-dimethoxyethane, or a mixture of these solvents, ata temperature between 0° C. and a temperature at which the solventrefluxes. Without isolating the active ester, a compound represented byformula (AD-1) can then be manufactured according to a method known fromliterature, for example, a method disclosed in “The Journal of theAmerican Chemical Society”, 75, pages 637-640, 1953, by adding a base,such as N,N-diisopropylethylamine, triethylamine or pyridine, andammonium carbonate to the reaction solution above and carrying out areaction at a temperature between 0° C. and a temperature at which thesolvent refluxes.

<Step 3>

A compound represented by formula (AD-1) can be manufactured accordingto a method known from literature, for example, a method disclosed inExample 43 on page 120 of WO 2006/043145 (published 27 Apr. 2006), bysubjecting the compound represented by formula (ET-1) to a reactionusing an aqueous ammonia solution at a temperature between 0° C. and atemperature at which the solvent refluxes.

WORKING EXAMPLES

Working examples and reference examples will now be given in order toexplain the present invention in greater detail, but the presentinvention is not limited to these examples.

Nuclear magnetic resonance (NMR) spectra measurements involved the useof a JEOL JNM-ECX400 FT-NMR (manufactured by JEOL Ltd.) and a (JEOLJNM-ECX300) FT-NMR (manufactured by JEOL Ltd.). LC-Mass measurementswere carried out using any of the methods below. A Waters Fraction LynxMS system (manufactured by Waters) was used, the column was a SunFirecolumn (4.6 mm×5 cm, 5 μm) manufactured by Waters, and the mobile phasewas a methanol: 0.05% acetic acid aqueous solution at a gradient of10:90 (0 min)-100:0 (2 min)-100:0 (3 min).

In the physical property data in the working examples, LC-MS meansLC-Mass, and in LC-MS measurements, M denotes molecular weight, RTdenotes retention time, and [M+H]⁺, [M+3H]³⁺ and [M+Na]⁺ denotemolecular ion peaks. In ¹H-NMR data, s denotes singlet, d denotesdoublet, t denotes triplet, q denotes quartet and m denotes multiplet inNMR signal patterns.

(Working Example 1) Synthesis of4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylic AcidEthyl Ester (alternative name: ethyl4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylate)

4-bromo-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester (CAS No.:1328640-39-6, 5 g, 21 mmol), dipalladium (0) tri(dibenzylideneacetone)(Pd₂(dba)₃) (0.39 g, 0.43 mmol),2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (0.35 g, 0.86mmol) and triethylamine (9.0 mL, 64 mmol) were mixed in toluene (25 mL),and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.1 mL, 21 mmol) was addedat room temperature. The obtained mixture was stirred for 45 minutes at90° C., 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.5 mL, 10.5 mmol) wasadded, and a reaction was carried out at the same temperature for 45minutes. Potassium carbonate (8.9 g, 64 mmol) was dissolved in water (10mL) and added slowly to the reaction mixture, after which4-chloro-2,5-dimethylpyrimidine (3.1 g, 21 mmol) and ethanol (20 mL)were added. The obtained mixture was refluxed for 2 hours, cooled toroom temperature, filtered with celite, and washed with ethyl acetateand water. The filtrate was extracted with 3N hydrochloric acid. Theaqueous layer was washed with methyl tert-butyl ether (MTBE), renderedbasic by means of potassium carbonate, and extracted usingdichloromethane. The organic layer was concentrated under reducedpressure, and crude4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylic acidethyl ester (4.1 g, 52% yield, 71% purity) was obtained as a brown oilysubstance.

(Physical property data) LC-MS: M=260, RT=0.83 (min), [M+H]⁺=261. ¹H-NMR(300 MHz, CDCl₃, δ ppm): 8.50 (1H, s), 7.56 (1H, s), 4.22 (3H, s), 4.17(2H, q, J=7 Hz), 2.72 (3H, s), 2.16 (2H, s), 1.05 (3H, t, J=7 Hz).

(Working Example 2) Separate Synthesis of4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide

4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylic acid(alternative name:4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylic acid)(0.5 g, 2.2 mmol), which was synthesized using a method similar to thatin <Step 1> in Working Example 5 below, and diisopropylethylamine (0.4mL, 2.4 mmol) was dissolved in tetrahydrofuran (5 mL), and ethylchloroformate (0.23 mL, 2.4 mmol) was added dropwise under ice cooling.After stirring for 20 minutes under ice cooling, ammonium carbonate(0.41 g, 4.3 mmol) and diisopropylethylamine (0.75 mL, 4.3 mmol) wereadded, and the obtained mixture was stirred for 45 minutes at roomtemperature. A saturated aqueous solution of sodium hydrogen carbonatewas added to the reaction mixture, and the reaction mixture was thenextracted using ethyl acetate. The organic layer was washed with water,washed with a saturated saline solution, dried using sodium sulfate, andthen concentrated under reduced pressure.4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide (0.37g, 73%) was obtained as a white solid. Data for the obtained4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide wasidentical to data for the4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamidesynthesized in <Step 1> in Working Example 6 below.

(Working Example 3) Synthesis of 5-fluoro-4-iodopyridine-2-amine

<Step 1> Synthesis of 2,5-difluoro-4-iodopyridine

Using 2,5-difluoro-4-pyridine, crude 2,5-difluoro-4-iodopyridine (crudeyield 96%) was obtained using a method similar to that disclosed in step(A) in Example 56 on page 116 of WO 2011/073845 (published 23 Jun. 2011)¹H NMR data for the obtained 2,5-difluoro-4-iodopyridine was identicalto data disclosed in WO 2011/073845.

<Step 2> Synthesis of 5-fluoro-4-iodopyridine-2-amine

Crude 2,5-difluoro-4-iodopyridine (2.26 g, 9.4 mmol), which was obtainedin <Step 1> in Working Example 3, 28% aqueous ammonia (6.8 mL) and1,4-dioxane (2.3 mL) were added to a sealed reaction vessel and heatedfor 53 hours using an oil bath at 135° C. Water was added to thereaction mixture, and the reaction mixture was then extracted usingmethyl tert-butyl ether (MTBE). The obtained organic layer was washedwith water and concentrated under reduced pressure. Crude5-fluoro-4-iodopyridine-2-amine (1.90 g, 85%) was obtained as a mossgreen-colored solid.

(Physical property data) LC-MS: M=238, RT=0.55 (min), [M+H]⁺=239. H NMR(400 MHz, DMSO-d₆, δ ppm): 7.82 (1H, s), 6.92 (1H, d, J=4 Hz), 6.00 (2H,s).

(Working Example 4) Synthesis of Benzyl(4-amino-5-fluoropyridin-2-yl)carbamate Hydrochloride

<Step 1> Synthesis of 2-bromo-5-fluoroisonicotinic Acid

n-butyl lithium (2.6 M hexane solution, 100 mL, 0.26 mol) was added to atetrahydrofuran solution (630 mL) of diisopropylamine (27 g, 0.26 mol)at a temperature of −60° C. or lower, and the obtained mixture wasstirred for 15 minutes at −70° C. A tetrahydrofuran solution (620 mL) of2-bromo-5-fluoropyridine (42 g, 0.24 mol) was added at a temperature of−60° C. or lower, and the obtained mixture was stirred for 90 minutes at−70° C. An appropriate quantity of dry ice was added at −70° C., afterwhich the temperature of the reaction mixture was allowed to increase toroom temperature. The reaction mixture was rendered acidic by adding 2Ndilute hydrochloric acid (400 mL), after which tetrahydrofuran wasdistilled off under reduced pressure. Precipitated crystals werefiltered off and washed with water, after which toluene was added, andthe obtained mixture was dried by means of azeotropic distillation.2-bromo-5-fluoroisonicotinic acid (48 g, 92%) was obtained as a whitesolid.

(Physical property data) LC-MS: M=219, RT=0.74 (min), [M+H]⁺=220,[M+3H]³⁺=222. ¹H-NMR (300 MHz, DMSO-d₆, δ ppm): 8.63 (1H, d, J=2 Hz),7.95 (1H, d, J=5 Hz).

<Step 2> Synthesis of 2-amino-5-fluoroisonicotinic Acid Hydrochloride

2-bromo-5-fluoroisonicotinic acid (10 g, 45 mmol), which was synthesizedusing a method similar to that in <Step 1> in Working Example 4, 28%aqueous ammonia (30 mL) and copper iodide (CuI) (0.43 g, 2.3 mmol) wereplaced in a sealed reaction vessel and heated for 17.5 hours using anoil bath at 120° C. Acetone (30 mL) was added, after which concentratedhydrochloric acid was added under ice cooling so as to obtain a pH of 4.Acetone (60 mL) was again added, and the obtained solid was filteredoff, washed with acetone, and dried at 45° C. Crude2-amino-5-fluoroisonicotinic acid hydrochloride (13 g, 148%, includingammonium salt) was obtained as a beige solid.

(Physical property data) LC-MS: M (free amine)=156, RT=0.17 (min),[M+H]⁺=157. ¹H-NMR (400 MHz, DMSO-d₆, δ ppm): 8.06 (1H, brs), 6.85 (1H,brs), 6.13 (2H, brs).

<Step 3> Synthesis of 2-amino-5-fluoroisonicotinic Acid Ethyl Ester

Crude 2-amino-5-fluoroisonicotinic acid hydrochloride (20 g, 104 mmol),which was synthesized using a method similar to that in <Step 2> inWorking Example 4, was suspended in ethanol (200 mL), and thionylchloride (38 mL, 520 mmol and N,N-dimethylformamide (DMF, 0.8 mL, 10mmol) were added under ice cooling. The obtained mixture was heated for5.75 hours at 80° C. After cooling the mixture, methyl tert-butyl ether(MTBE) (400 mL) was added, and a precipitated solid was filtered off andwashed with methyl tert-butyl ether (MTBE). The obtained solid wasdissolved in ethyl acetate and washed with a saturated aqueous solutionof sodium hydrogen carbonate. The aqueous layer was extracted usingethyl acetate, and the obtained organic layer was combined with theorganic layer mentioned above and washed with dilute aqueous ammonia,water and a saturated saline solution in that order. The organic layerwas dried using sodium sulfate and concentrated under reduced pressure.The obtained solid was suspended in heptadecane, filtered off and dried.2-amino-5-fluoroisonicotinic acid ethyl ester (19 g, 98%) was obtainedas a beige solid.

(Physical property data) LC-MS: M=184, RT=0.68 (min), [M+H]⁺=185. ¹H-NMR(300 MHz, DMSO-d₆, δ ppm): 8.01 (1H, d, J=3 Hz), 6.82 (1H, d, J=6 Hz),6.18 (2H, s), 4.31 (2H, q, J=7 Hz), 1.29 (3H, t, J=7 Hz).

<Step 4> Synthesis of2-(((benzyloxy)carbonyl)amino)-5-fluoroisonicotinic Acid Ethyl Ester

Benzyl chlorocarbonate (5.0 mL, 35 mmol) was added under ice cooling toa pyridine solution (40 mL) of 2-amino-5-fluoroisonicotinic acid ethylester (5.0 g, 27 mmol), which was synthesized in <Step 3> in WorkingExample 4. The obtained mixture was stirred for 4 hours at 25° C., afterwhich benzyl chlorocarbonate (3.1 mL) was added. Water was added to thereaction mixture, and a precipitated solid was filtered off and washedwith water. The obtained solid was suspended in a mixed solvent (1:1) ofmethyl tert-butyl ether (MTBE) and heptane, filtered off and dried.2-(((benzyloxy)carbonyl)amino)-5-fluoroisonicotinic acid ethyl ester(7.6 g, 88%) was obtained as a white solid.

(Physical property data) LC-MS: M=318, RT=1.12 (min), [M+Na]⁺=341.¹H-NMR (300 MHz, DMSO-d₆, δ ppm): 10.6 (1H, s), 8.46 (1H, d, J=3 Hz),8.26 (1H, d, J=6 Hz), 7.45-7.31 (5H, m), 5.19 (2H, s), 4.36 (2H, q, J=7Hz), 1.32 (3H, t, J=7 Hz).

<Step 5> Synthesis of2-(((benzyloxy)carbonyl)amino)-5-fluoroisonicotinic Acid

A 1N aqueous solution of sodium hydroxide (26 mL) was added under icecooling to an ethanol suspension of2-(((benzyloxy)carbonyl)amino)-5-fluoroisonicotinic acid ethyl ester(7.5 g, 23 mmol), which was synthesized in <Step 4> in Working Example4. The obtained suspension was stirred for 4 hours at room temperature.Water was added, after which the pH was adjusted to 4 to 5 by means ofconcentrated hydrochloric acid. The obtained solid was filtered off,washed with water and dried.2-(((benzyloxy)carbonyl)amino)-5-fluoroisonicotinic acid (6.4 g, 93%)was obtained as a white solid.

(Physical property data) LC-MS: M=290, RT=0.98 (min), [M+H]⁺=291,[M+Na]⁺=313. ¹H-NMR (400 MHz, DMSO-d₆, δ ppm): 10.6 (1H, s), 8.42 (1H,d, J=4 Hz), 8.24 (1H, d, J=8 Hz), 7.44-7.31 (5H, m), 5.19 (2H, s).

<Step 6> Synthesis of benzyltert-butyl(5-fluoropyridin-2,4-diyl)dicarbamate

2-(((benzyloxy)carbonyl)amino)-5-fluoroisonicotinic acid (0.19 g, 0.65mmol), which was synthesized in <Step 5> in Working Example 4, wassuspended in tert-butanol (2.85 mL), and triethylamine (0.27 mL, 2.0mmol) was then added. The obtained mixture was heated, anddiphenylphosphoryl azide (0.16 mL, 0.72 mmol) was added dropwise at 80°C. After heating for 4 hours at 80° C., diphenylphosphoryl azide (0.03mL) was added. Heptane (2 mL) was added, and the obtained solid wasfiltered off, washed with heptane and then dried. Benzyltert-butyl(5-fluoropyridin-2,4-diyl)dicarbamate (0.21 g, 87%) wasobtained as a white solid.

(Physical property data) LC-MS: M=361, RT=1.1 (min), [M+Na]⁺=384. ¹H-NMR(400 MHz, DMSO-d₆, δ ppm): 10.2 (1H, s), 9.57 (1H, s), 8.49 (1H, d, J=8Hz), 8.11 (1H, d, J=3 Hz), 7.43-7.31 (5H, m), 5.16 (2H, s), 1.49 (9H,s).

<Step 7> Synthesis of Benzyl (4-amino-5-fluoropyridin-2-yl)carbamateHydrochloride

Benzyl tert-butyl (5-fluoropyridin-2,4-diyl)dicarbamate (0.19 g, 0.53mmol), which was synthesized in <Step 6> in Working Example 4, wassuspended in 1,4-dioxane (1.9 mL), and a 4N hydrochloric acid solution(1,4-dioxane solution: 0.39 mL) was added. The obtained mixture wasstirred at room temperature and then stirred for 3.5 hours at 60° C.,and a 4N hydrochloric acid solution (1,4-dioxane solution: 0.39 mL) wasthen added. Methyl tert-butyl ether (MTBE) (5 mL) was added, theobtained solid was filtered off, washed with methyl tert-butyl ether(MTBE) and dried, and benzyl (4-amino-5-fluoropyridin-2-yl)carbamatehydrochloride (0.15 g, 93%) was obtained as a white solid.

(Physical property data) LC-MS: M=261, RT=0.76 (min), [M+Na]⁺=284.¹H-NMR (400 MHz, DMSO-d₆, δ ppm): 11.4 (1H, s), 8.10 (1H, d, J=4 Hz),8.07 (2H, brs), 7.46-7.35 (5H, m), 6.79 (1H, d, J=8 Hz), 5.24 (2H, s).

(Working Example 5) Synthesis ofN-(2-amino-5-fluoropyridin-4-yl)-4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide

<Step 1> Synthesis of4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylic acid(Alternative Name:4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylic Acid)

A 1N aqueous solution of sodium hydroxide (19 mL, 19 mmol) and toluene(20 mL) were added to crude4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylic acidethyl ester (4.0 g, 16 mmol), which was synthesized in Working Example1, and the obtained mixture was stirred for 5 hours at room temperature.The aqueous layer was separated and adjusted to a pH of 1 by addingconcentrated hydrochloric acid. A precipitated solid was filtered off,washed with water and dried, and4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylic acid(2.4 g, 65%) was obtained as a pale yellow solid.

(Physical property data) LC-MS: M=232, RT=0.65 (min), [M+H]⁺=233. ¹H-NMR(400 MHz, DMSO-d₆, δ ppm): 8.49 (1H, s), 7.61 (1H, s), 4.07 (3H, s),2.55 (3H, s), 2.15 (3H, s).

<Step 2> Synthesis of Benzyl(4-(4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide)-5-fluoropyridin-2-yl)carbamate

Benzyl (4-amino-5-fluoropyridin-2-yl) carbamate hydrochloride (50 mg,0.17 mmol), which was synthesized using a method similar to that inWorking Example 4, was dissolved in N-methylpyrrolidone (NMP) (0.4 mL)and 2,6-lutidine (0.06 mL), and4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylic acid(47 mg, 0.2 mmol), which was synthesized using a method similar to thatin <Step 1> in Working Example 5, andO-(7-aza-1H-benzotriazol-1-yl)-N,N,N,N′,N′-tetramethyl uroniumhexafluorophosphate (HATU, CAS No.: 148893-10-1) (89 mg, 0.24 mmol) wereadded. The obtained mixture was stirred for 54 hours at 60° C., andlutidine 2,6-lutidine (0.11 mL) and HATU (0.18 g) were then added. Water(1 mL) was added, and the obtained mixture was stirred for 2 hours atroom temperature. The obtained solid was filtered off, washed withwater, suspended again in ethanol, filtered off, washed with ethanol anddried, and benzyl(4-(4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide)-5-fluoropyridin-2-yl)carbamate(64 mg, 80%) was obtained as a beige solid.

(Physical property data) LC-MS: M=475, RT=1.1 (min), [M+H]⁺=476,[M+Na]⁺=498. ¹H-NMR (400 MHz, DMSO-d₆, δ ppm): 10.9 (1H, s), 10.3 (1H,s), 8.67 (1H, brs), 8.55 (1H, s), 8.25 (1H, d, J=4 Hz), 8.00 (1H, s),7.43-7.31 (5H, m), 5.17 (2H, s), 4.01 (3H, s), 2.38 (3H, s), 2.37 (3H,s).

<Step 3> Synthesis ofN-(2-amino-5-fluoropyridin-4-yl)-4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide

Benzyl(4-(4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide)-5-fluoropyridin-2-yl)carbamate(50 mg, 0.11 mmol), Which was synthesized using a method similar to thatin <Step 2> in Working Example 5, was dissolved in dichloromethane (0.75mL) and methanol (0.25 mL), palladium-carbon (5 mg) was added, and theobtained mixture was stirred for 6.5 hours at room temperature in ahydrogen gas atmosphere. The palladium-carbon was removed by filtration,the obtained liquid was concentrated under reduced pressure, andN-(2-amino-5-fluoropyridin-4-yl)-4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide(33 mg, 92%) was obtained as a pale yellow solid.

(Physical property data) LC-MS: M=341, RT=0.67 (min), [M+H]⁺=342. ¹H-NMR(400 MHz, DMSO-d₆, δ ppm): 10.7 (1H, s), 8.56 (1H, s), 7.98 (1H, s),7.84 (1H, d, J=3 Hz), 7.29 (1H, brs), 5.95 (2H, s), 4.00 (3H, s), 2.43(3H, s), 2.36 (3H, s).

(Working Example 6) Synthesis of4-(2,5-dimethylpyrimidin-4-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

<Step 1> Synthesis of4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide

A mixture of crude4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylic acidethyl ester (0.50 g, 1.9 mmol), which was synthesized using a methodsimilar to that in Working Example 1, and 25% aqueous ammonia (5 mL) wasstirred for 20 hours at room temperature. A saturated aqueous solutionof sodium hydrogen carbonate was added to the reaction mixture, and thereaction mixture was then extracted using ethyl acetate. The obtainedorganic layer was washed with a saturated saline solution, dried usingsodium sulfate, and then concentrated under reduced pressure.4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide (0.13g, 30%) was obtained as a pale yellow solid.

(Physical property data) LC-MS: M=231, RT=0.54 (min), [M+H]⁺=232. ¹H-NMR(300 MHz, DMSO-d₆, δ ppm): 8.57 (1H, s), 8.28 (1H, brs), 7.84 (1H, s),7.79 (1H, brs), 3.98 (3H, s), 2.56 (3H, s), 2.30 (2H, s).

<Step 2> Synthesis ofN-(2-amino-5-fluoropyridin-4-yl)-4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide

Crude 5-fluoro-4-iodopyridine-2-amine (104 mg, 0.44 mmol), which wassynthesized in Working Example 3,4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide (92mg, 0.4 mmol), which was synthesized in Working Example 2,N,N′-dimethyl-1,2-ethanediamine (4.1 mg, 0.05 mmol), copper iodide (CuI)(9.1 mg, 0.05 mmol) and potassium carbonate (110 mg, 0.8 mmol) weremixed in 1,4-dioxane (1 mL), and heated for 20 hours using an oil bathat 100° C. Crude 5-fluoro-4-iodopyridine-2-amine (16 mg, 0.07 mmol),N,N′-dimethyl-1,2-ethanediamine (2 mg, 0.02 mmol) and copper iodide(CuI) (4 mg, 0.02 mmol) were added, the obtained mixture was heated for6 hours using an oil bath at 100° C., after which crude5-fluoro-4-iodopyridine-2-amine (16 mg, 0.07 mmol) was added, and theobtained mixture was heated and stirred for 15 hours. Water anddichloromethane were added to the reaction mixture, insoluble substanceswere removed by filtration, and the organic layer was then separated.The obtained organic layer was washed with water and concentrated underreduced pressure. The obtained solid was washed with methyl tert-butylether (MTBE) in order to remove excess 5-fluoro-4-iodopyridine-2-amine,andN-(2-amino-5-fluoropyridin-4-yl)-4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide(82 mg, 60%) was obtained as a brown solid. Data for the obtainedN-(2-amino-5-fluoropyridin-4-yl)-4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamidewas identical to the data for theN-(2-amino-5-fluoropyridin-4-yl)-4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamidesynthesized in <Step 3> in Working Example 5.

<Step 3> Synthesis ofN-(2-benzimidamido-5-fluoropyridin-4-yl)-4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide

Pyridine (0.5 mL) and dimethyl sulfoxide (0.25 mL) were added to amixture ofN-(2-amino-5-fluoropyridin-4-yl)-4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide(100 mg, 0.29 mmol), which was synthesized using a method similar tothat in <Step 3> in Working Example 5 or <Step 2> in Working Example 6,and methylbenzimidothioate hydroiodide (106 mg, 0.38 mmol). The obtainedsolution was stirred for 7 hours in an oil bath at 80° C. Acetone (0.5mL), a saturated aqueous solution of sodium hydrogen carbonate (0.5 mL)and water (2 mL) were added to the reaction mixture and stirred for 1hour at room temperature. The obtained solid was filtered off, washedwith water and dried, andN-(2-benzimidamido-5-fluoropyridin-4-yl)-4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide(112 mg, 86%) was obtained as a white-yellow solid.

(Physical property data) LC-MS: M=444, RT=0.81 (min), [M+H]⁺=445. ¹H-NMR(400 MHz, DMSO-d₆, δ ppm): 10.9 (1H, s), 9.86 (1H, brs), 8.57 (1H, s),8.31 (1H, d, J=2 Hz), 8.03-8.01 (3H, m), 7.92 (1H, brs), 7.67-7.47 (3H,m), 4.02 (3H, s), 2.41 (3H, s), 2.37 (3H, s).

<Step 4> Synthesis of4-(2,5-dimethylpyrimidin-4-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

N-(2-benzimidamido-5-fluoropyridin-4-yl)-4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide(200 mg, 0.45 mmol), which was synthesized using a method similar tothat in <Step 3> in Working Example 6, and a copper chloride (CuCl)catalyst (4.5 mg, 0.04 mmol) were mixed in pyridine (0.8 mL), and theobtained mixture was stirred in air for 2.5 hours using an oil bath at100° C. 28% aqueous ammonia (0.2 mL) and water were added, and theobtained suspension was stirred for 10 minutes under ice cooling. Thegenerated solid was filtered off, washed with water and dried, and4-(2,5-dimethylpyrimidin-4-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide(159 mg, 80%) was obtained as an off-white solid.

(Physical property data) LC-MS: M=442, RT=1.13 (min), [M+H]⁺=443. ¹H-NMR(400 MHz, CDCl₃, δ ppm): 11.72 (1H, s), 8.78 (1H, d, J=8 Hz), 8.63 (1H,s), 8.59 (1H, d, J=8 Hz), 8.27-8.24 (2H, m), 7.70 (1H, s), 7.51-7.49(3H, m), 4.31 (3H, s), 2.78 (3H, s), 2.42 (3H, s).

(Working Example 7) Synthesis of methyl1-methyl-4-(2-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxylate

Using 4-bromo-1-methyl-1H-pyrazole-5-carboxylic acid methyl ester (CASNo.: 514816-42-3, 2.0 g, 9.1 mmol) and 4-chloro-2-methylpyrimidine (0.94g), methyl 1-methyl-4-(2-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxylate(1.26 g) was obtained as a yellow oily substance using a method similarto that in <Step 1> in Working Example 1 or a method based on thismethod.

(Physical property data) LC-MS: M=232, RT=0.75 (min), [M+H]⁺=233. ¹H-NMR(300 MHz, CDCl₃, δ ppm) 8.62 (1H, d, J=5 Hz), 7.85 (1H, s), 7.29 (1H, d,J=5 Hz), 4.15 (3H, s), 3.87 (3H, s), 2.74 (3H, s).

(Working Example 8) Synthesis of1-methyl-4-(2-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxylic Acid

Using methyl1-methyl-4-(2-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxylate (1.26 g),which was obtained in Working Example 7, the title compound (682 mg) wasobtained as a colorless solid using a method similar to that in <Step 1>in Working Example 5 or a method based on this method.

(Physical property data) LC-MS: M=218, RT=0.67 (min), [M+H]⁺=219. ¹H-NMR(300 MHz, CDCl₃, δ ppm): 8.79 (1H, d, J=6 Hz), 8.09 (1H, s), 7.56 (1H,d, J=6 Hz), 4.36 (3H, s), 2.81 (3H, s).

(Working Example 9) Synthesis of1-methyl-4-(2-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxamide

1-methyl-4-(2-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxylic acid (2.0g, 9.2 mmol), which was synthesized using a method similar to that inWorking Example 8, and diisopropylethylamine (1.8 mL, 10 mmol) weresuspended in tetrahydrofuran (20 mL), and benzyl chloroformate (1.7 mL,10 mmol) was added dropwise under ice cooling. After stirring for 30minutes under ice cooling, ammonium carbonate (1.8 g, 18 mmol) anddiisopropylethylamine (3.2 mL, 18 mmol) were added, and the obtainedmixture was stirred for 1.25 hours at room temperature. An aqueoussolution of sodium hydrogen carbonate was added to the reaction mixture,and the reaction mixture was extracted using ethyl acetate. The solid inthe aqueous layer was filtered off, and the obtained aqueous layer wasextracted using ethyl acetate. The organic layer was added, washed withwater, washed with a saturated saline solution, dried using sodiumsulfate, and then concentrated under reduced pressure. The obtainedsolid residue and the solid obtained from the aqueous layer werecombined, the obtained mixture was triturated with methyl tert-butylether (MTBE), filtered off, washed with MTBE and dried, and1-methyl-4-(2-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxamide (1.2 g,59%) was obtained as a white solid.

(Physical property data) LC-MS: M=217, RT=0.57 (min), [M+H]⁺=218. ¹H-NMR(400 MHz, DMSO-d₆, δ ppm): 9.17 (1H, s), 8.66 (1H, d, J=6 Hz), 8.12 (1H,s), 8.03 (1H, s), 7.54 (1H, d, J=6 Hz), 3.96 (3H, s), 2.60 (3H, s).

(Working Example 10) Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(2-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxamide

<Step 1> Synthesis ofN-(2-amino-5-fluoropyridin-4-yl)-1-methyl-4-(2-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxamide

5-fluoro-4-iodopyridine-2-amine (482 mg, 2.0 mmol), which wassynthesized using a method similar to that in Working Example 3, and1-methyl-4-(2-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxamide (400 mg,1.8 mmol), which was synthesized in Working Example 9, were subjected toa reaction using a method based on <Step 2> in Working Example 6, afterwhich a 28% aqueous solution of ammonia (0.8 mL) was added, and theobtained mixture was stirred at room temperature, and then diluted withwater. The precipitated solid was filtered off, washed with water anddried, the obtained crude product was triturated in ethylacetate/ethanol/MTBE (1:2:10), andN-(2-amino-5-fluoropyridin-4-yl)-1-methyl-4-(2-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxamide(299 mg, 50%) was obtained as a white solid.

(Physical property data) LC-MS: M=327, RT=0.69 (min), [M+H]⁺=328. ¹H-NMR(400 MHz, DMSO-d₆, δ ppm): 11.6 (1H, s), 8.68 (1H, d, J=5 Hz), 8.22 (1H,s), 7.87 (1H, d, J=2 Hz), 7.66 (1H, d, J=5 Hz), 7.30 (1H, s), 5.90 (2H,s), 4.00 (3H, s), 2.49 (3H, s).

<Step 2> Synthesis ofN-(2-benzimidamido-5-fluoropyridin-4-yl)-1-methyl-4-(2-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxamide

UsingN-(2-amino-5-fluoropyridin-4-yl)-1-methyl-4-(2-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxamide(290 mg, 0.89 mmol), which was synthesized using a method similar tothat in <Step 1> in Working Example 10, and methylbenzimidothioatehydroiodide (322 mg, 1.2 mmol; 74 mg, 0.27 mmol; or 49 mg, 0.18 mmol),N-(2-benzimidamido-5-fluoropyridin-4-yl)-1-methyl-4-(2-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxamide(368 mg, 97%) was obtained as a gray solid using a method similar tothat in <Step 3> in Working Example 6.

(Physical property data) LC-MS: M=430, RT=0.84 (min), [M+H]⁺=431. ¹H-NMR(400 MHz, DMSO-d₆, δ ppm): 11.8 (1H, s), 9.80 (1H, s), 8.70 (1H, d, J=6Hz), 8.35 (1H, d, J=1 Hz), 8.27 (1H, s), 8.04 (2H, d, J=7 Hz), 7.91 (1H,d, J=5 Hz), 7.68 (1H, d, J=5 Hz), 7.53-7.46 (3H, m), 4.03 (3H, s), 2.49(3H, s).

<Step 3> Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1l-methyl-4-(2-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxamide

UsingN-(2-benzimidamido-5-fluoropyridin-4-yl)-1-methyl-4-(2-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxamide(320 mg, 0.74 mmol), which was synthesized in <Step 2> in WorkingExample 10,N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1l-methyl-4-(2-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxamide(263 mg, 83%) was obtained as a beige solid using a method similar tothat in <Step 4> in Working Example 6.

(Physical property data) LC-MS: M=428, RT=1.16 (min), [M+H]⁺=429. ¹H-NMR(400 MHz, CDCl₃, δ ppm): 13.39 (1H, s), 8.75-8.64 (3H, m), 8.28-8.26(2H, m), 7.96 (1H, s), 7.52-7.47 (4H, m), 4.36 (3H, s), 2.79 (3H, s).

(Working Example 11) Synthesis of methyl4-(5-fluoro-2-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylate

Using 4-bromo-1-methyl-1H-pyrazole-5-carboxylic acid methyl ester (CASNo.: 514816-42-3, 2.52 g, 11.5 mmol) and4-chloro-5-fluoro-2-methoxypyrimidine (1.5 g), methyl4-(5-fluoro-2-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylate(1.6 g) was obtained as a pale yellow liquid using a method similar tothat in <Step 1> in Working Example 1 or a method based on this method.

(Physical property data) LC-MS: M=266, RT=0.91 (min), [M+H]⁺=267. ¹H-NMR(300 MHz, CDCl₃, δ ppm): 8.35 (1H, d, J=2 Hz), 7.86 (1H, d, J=1 Hz),4.15 (3H, s), 4.00 (3H, s), 3.86 (3H, s).

(Working Example 12) Synthesis of4-(5-fluoro-2-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylicAcid

Using methyl4-(5-fluoro-2-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylate(1.6 g), which was obtained in Working Example 11,4-(5-fluoro-2-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylicacid (0.65 g) was obtained as a colorless solid using a method similarto that in <Step 1> in Working Example 5 or a method based on thismethod.

(Physical property data) LC-MS: M=252, RT=0.81 (min), [M+Na]⁺=275.¹H-NMR (300 MHz, CDCl₃, δ ppm): 8.54 (1H, d, J=3 Hz), 8.28 (1H, d, J=4Hz), 4.36 (3H, s), 4.09 (3H, s).

(Working Example 13) Synthesis of4-(5-fluoro-2-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide

Using4-(5-fluoro-2-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylicacid (0.50 g, 2.0 mmol), which was synthesized using a method similar tothat in Working Example 12, and ethyl chloroformate (0.21 mL, 2.2 mmol),4-(5-fluoro-2-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide(0.40 g, 80%) was obtained as a white solid using a method similar tothat in Working Example 9.

(Physical property data) LC-MS: M=251, RT=0.67 (min), [M+H]⁺=252. ¹H-NMR(400 MHz, DMSO-d₆, δ ppm): 8.64 (1H, d, J=3 Hz), 8.18 (1H, s), 7.97 (1H,s), 7.95 (1H, d, J=3 Hz), 3.90 (3H, s), 3.89 (3H, s).

(Working Example 14) Synthesis of4-(5-fluoro-2-methoxypyrimidin-4-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

<Step 1> Synthesis ofN-(2-amino-5-fluoropyridin-4-yl)-4-(5-fluoro-2-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide

5-fluoro-4-iodopyridine-2-amine (104 mg, 0.44 mmol), which wassynthesized using a method similar to that in Working Example 3,4-(5-fluoro-2-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide(100 mg, 0.4 mmol), which was synthesized in Working Example 13,trans-N,N′-dimethylcyclohexane-1,2-diamine (34 mg, 0.24 mmol), copperiodide (CuI) (23 mg, 0.12 mmol) and potassium phosphate (169 mg, 0.8mmol) were mixed in dimethyl sulfoxide (1 mL), and heated for 3.7 hoursat 60° C. A 28% aqueous solution of ammonia (0.2 mL) was added, and theobtained mixture was stirred at room temperature and then diluted withwater. The reaction mixture was extracted using methylene chloride, andthe obtained organic layer was washed with water and a saline solution,dried using sodium sulfate, and concentrated. The obtained solid residuewas triturated with methyl tert-butyl ether (MTBE), filtered off, washedwith methyl tert-butyl ether, and dried, andN-(2-amino-5-fluoropyridin-4-yl)-4-(5-fluoro-2-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide(99 mg, 69%) was obtained as a gray solid.

(Physical property data) LC-MS: M=361, RT=0.71 (min), [M+H]⁺=362.

¹H-NMR (400 MHz, DMSO-d₆, δ ppm): 10.8 (1H, s), 8.65 (1H, d, J=3 Hz),8.02 (1H, d, J=3 Hz), 7.84 (1H, s), 7.37 (1H, d, J=5 Hz), 5.91 (2H, s),3.92 (3H, s), 3.68 (3H, s).

<Step 2> Synthesis ofN-(2-benzimidamido-5-fluoropyridin-4-yl)-4-(5-fluoro-2-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide

Pyridine (0.4 mL) and dimethyl sulfoxide (0.2 mL) were added to amixture ofN-(2-amino-5-fluoropyridin-4-yl)-4-(5-fluoro-2-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide(80 mg, 0.22 mmol), which was synthesized in <Step 1> in Working Example14, and methylbenzimidothioate hydroiodide (80 mg, 0.29 mmol). Theobtained solution was stirred for 35 minutes at 80° C., andmethylbenzimidothioate hydroiodide (12 mg, 0.04 mmol) was added andstirred for a further 40 minutes. Acetone (0.4 mL) and a saturatedaqueous solution of sodium hydrogen carbonate (0.4 mL) were added to thereaction mixture, the reaction mixture was stirred for 30 minutes atroom temperature, after which water (1.6 mL) was added, and the reactionmixture was stirred for a further 1 hour. The obtained solid wasfiltered off, washed with water and dried, andN-(2-benzimidamido-5-fluoropyridin-4-yl)-4-(5-fluoro-2-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide(86 mg, 84%) was obtained as a gray solid.

(Physical property data) LC-MS: M=464, RT=0.82 (min), [M+H]⁺=465. ¹H-NMR(400 MHz, DMSO-d₆, δ ppm): 11.1 (1H, s), 8.67 (1H, d, J=3 Hz), 8.30 (1H,s), 8.07-8.01 (3H, m), 7.99-7.90 (1H, m), 7.54-7.45 (3H, m), 3.97 (3H,s), 3.68 (3H, s).

<Step 3> Synthesis of4-(5-fluoro-2-methoxypyrimidin-4-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide

N-(2-benzimidamido-5-fluoropyridin-4-yl)-4-(5-fluoro-2-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide(70 mg, 0.15 mmol), which was synthesized in <Step 2> in Working Example14, and a copper chloride (CuCl) catalyst (1.5 mg, 0.02 mmol) were mixedin pyridine (0.28 mL), and the obtained mixture was stirred in air for3.5 hours at 100° C. 28% aqueous ammonia (0.07 mL) and water were added,and the obtained suspension was stirred for 45 minutes at roomtemperature. The generated solid was filtered off, washed with water anddried, and4-(5-fluoro-2-methoxypyrimidin-4-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide(56 mg, 80%) was obtained as a beige solid.

(Physical property data) LC-MS: M=462, RT=1.10 (min), [M+H]⁺=463. ¹H-NMR(400 MHz, DMSO-d₆, δ ppm): 11.3 (1H, s), 9.45 (1H, d, J=6 Hz), 8.69 (1H,d, J=3 Hz), 8.57 (1H, d, J=7 Hz), 8.20-8.17 (2H, m), 8.08 (1H, d, J=3Hz), 7.57-7.49 (3H, m), 4.00 (3H, s), 3.67 (3H, s).

(Working Example 15) Synthesis of methyl1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxylate<Step 1> Synthesis ofmethyl-4-(5,5-dimethyl-1,3,2-dioxaborinan)-2-yl)-1-methyl-1H-pyrazole-5-carboxylate

A 1,1′-bis(diphenylphosphino) ferrocene-palladium (II) dichloridedichloromethane complex (0.37 g, 0.46 mmol) and potassium acetate (3.6g, 37 mmol) were added to a dimethyl sulfoxide solution (10 mL) of4-bromo-1-methyl-1H-pyrazole-5-carboxylic acid methyl ester (CAS No.:514816-42-3, 2.0 g, 9.1 mmol) and5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (4.1 g, 18 mmol), andstirred for 4 hours at 100° C. in a nitrogen atmosphere. The reactionsolution was cooled, water (50 mL) was added, and the reaction solutionwas extracted twice using ethyl acetate (100 mL). An organic layer wascombined, and the obtained mixture was washed with water and a saturatedsaline solution in that order, and then dried with anhydrous sodiumsulfate. A residue obtained by distilling of the solvent under reducedpressure was purified by means of silica gel column chromatography(silica gel:eluate; heptane:ethyl acetate 90:10 to 40:60), and the titlecompound (1.0 g) was obtained as a brown solid.

(Physical property data) LC-MS: M=252, RT=0.67 (min), [M+H]⁺ ofcorresponding boronic acid=185. ¹H-NMR (300 MHz, CDCl₃, δ ppm): 7.58(1H, s), 4.11 (3H, s), 3.88 (3H, s), 3.74 (4H, s), 1.05 (6H, s).

<Step 2> Synthesis of methyl1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxylate

Usingmethyl-4-(5,5-dimethyl-1,3,2-dioxaborinan)-2-yl)-1-methyl-1H-pyrazole-5-carboxylate(300 mg, 1.19 mmol), which was synthesized in <Step 1> in WorkingExample 15, and 2-bromo-4-(trifluoromethyl)thiazole (291 mg), methyl1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxylate(259 mg) was obtained as a light brown solid using a method similar tothat in <Step 1> in Working Example 1 or a method based on this method.

(Physical property data) LC-MS: M=291, RT=1.05 (min), [M+H]⁺=292. ¹H-NMR(400 MHz, CDCl₃, δ ppm): 8.11 (1H, s), 7.77-7.76 (1H, m), 4.21 (3H, s),3.98 (3H, s).

(Working Example 16) Synthesis of1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxylicAcid

2-yl)-1H-pyrazole-5-carboxylate (210 mg), which was obtained in WorkingExample 15,1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxylicacid (173 mg) was obtained as a brown-white solid using a method similarto that in <Step 1> in Working Example 5 or a method based on thismethod.

(Physical property data) LC-MS: M=277, RT=4.98 (min), [M+H]⁺=278. ¹H-NMR(400 MHz, CDCl₃, δ ppm): 8.48-8.46 (1H, m), 8.08 (1H, s), 4.12 (3H, s).

(Working Example 17) Synthesis of1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxamide

Using1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxylicacid (0.15 g, 0.54 mmol), which was synthesized using a method similarto that in Working Example 16, and ethyl chloroformate (0.057 mL, 0.6mmol),1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxamide(66 mg, 44%) was obtained as a white solid using a method similar tothat in Working Example 9.

(Physical property data) LC-MS: M=276, RT=0.90 (min), [M+H]⁺=277. ¹H-NMR(400 MHz, DMSO-d₆, δ ppm): 8.65 (1H, s), 8.44 (1H, q, J=1 Hz), 8.12 (1H,s), 8.02 (1H, s), 3.96 (3H, s).

(Working Example 18) Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxamide

<Step 1> Synthesis ofN-(2-amino-5-fluoropyridin-4-yl)-1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxamide

5-fluoro-4-iodopyridine-2-amine (38 mg, 0.16 mmol), which wassynthesized using a method similar to that in Working Example 3, and1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxamide(40 mg, 0.14 mmol), which was synthesized in Working Example 17, weresubjected to a reaction using a method based on <Step 2> in WorkingExample 6, after which a 28% aqueous solution of ammonia (0.08 mL) wasadded, stirred at room temperature, diluted with water, and extractedusing methylene chloride. The obtained organic layer was washed withwater and a saline solution, dried with sodium sulfate, and thenconcentrated. The obtained solid residue was triturated in MTBE, andN-(2-amino-5-fluoropyridin-4-yl)-1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxamide(33 mg, 59%) was obtained as a beige solid.

(Physical property data) LC-MS: M=386, RT=0.86 (min), [M+H]⁺=387. ¹H-NMR(400 MHz, DMSO-d₆, δ ppm): 11.2 (1H, s), 8.46 (1H, s), 8.13 (1H, s),7.87 (1H, s), 7.32 (1H, d, J=4 Hz), 5.94 (2H, s), 4.02 (3H, s).

<Step 2> Synthesis ofN-(2-benzimidamido-5-fluoropyridin-4-yl)-1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxamide

UsingN-(2-amino-5-fluoropyridin-4-yl)-1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxamide(25 mg, 0.06 mmol), which was synthesized in <Step 1> in Working Example18, and methylbenzimidothioate hydroiodide (23 mg, 0.08 mmol; or 3.6 mg,0.01 mmol),N-(2-benzimidamido-5-fluoropyridin-4-yl)-1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxamide(27 mg, 85%) was obtained as a beige solid using a method similar tothat in <Step 3> in Working Example 6.

(Physical property data) LC-MS: M=489, RT=0.95 (min), [M+H]⁺=490. ¹H-NMR(400 MHz, DMSO-d₆, δ ppm): 11.4 (1H, s), 9.82 (1H, s), 8.46 (1H, s),8.33 (1H, s), 8.16 (1H, s), 8.04 (2H, d, J=6 Hz), 7.89 (1H, s),7.53-7.45 (3H, m), 4.06 (3H, s).

<Step 3> Synthesis ofN-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1l-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxamide

UsingN-(2-benzimidamido-5-fluoropyridin-4-yl)-1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxamide(20 mg, 0.04 mmol), which was synthesized in <Step 2> in Working Example18,N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1l-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxamide(15 mg, 75%) was obtained as a beige solid using a method similar tothat in <Step 4> in Working Example 6.

(Physical property data) LC-MS: M=487, RT=1.25 (min), [M+H]⁺=488. ¹H-NMR(400 MHz, CDCl₃, δ ppm): 12.32 (1H, s), 8.86-8.80 (1H, m), 8.65-8.60(1H, m), 8.30-8.22 (2H, m), 7.96-7.90 (1H, m), 7.85-7.80 (1H, m),7.54-7.43 (3H, m), 4.37 (3H, s).

INDUSTRIAL APPLICABILITY

Provided by the present invention is a method for manufacturing acompound represented by formula (I), which has a short process and issuitable for industrial manufacturing. Also provided by the presentinvention is a synthesis intermediate that is useful for thismanufacturing method.

1. A method for manufacturing a compound represented by formula (AD-2)below:

in formula (AD-2), p denotes an integer between 0 and 3; R¹ groups eachindependently denote a group arbitrarily selected from among a halogenatom, a cyano group, a C₁₋₆ alkyl group, a C₃₋₈ cycloalkyl group, ahalogenated C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₁₋₆ alkoxy group,a C₁₋₆ alkoxy-C₁₋₆ alkyl group, a hydroxy-C₁₋₆ alkyl group and a C₂₋₇alkanoyl group; R² denotes a C₁₋₆ alkyl group; R³ denotes a grouparbitrarily selected from among a hydrogen atom and a fluorine atom; andring A group represented by formula (II):

denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarilyselected from among a thiazol-2-yl group, a thiazol-4-yl group, a1-methyl-1H-imidazol-4-yl group, a 1,3,4-thiadiazol-2-yl group, a1,2,4-thiadiazol-5-yl group, a pyridin-2-yl group, a pyridazin-3-ylgroup, a pyrimidin-2-yl group, a pyrimidin-4-yl group and a pyrazin-2-ylgroup, the manufacturing method comprising stages in which a compoundrepresented by formula (AD-1):

in formula (AD-1), p, R¹, R² and ring A group represented by formula(II) are defined in the same way as for formula (AD-2); and a2-amino-4-iodopyridine derivative represented by formula (PY-1):

in formula (PY-1), R³ denotes a group arbitrarily selected from among ahydrogen atom and a fluorine atom are reacted with each other using asolvent which does not take part in the reaction and which is selectedfrom the group consisting of 1,4-dioxane, tetrahydrofuran and1,2-dimethoxyethane at a temperature between 0° C. and a temperature atwhich the solvent refluxes in the presence ofN,N-dimethyl-1,2-ethanediamine, copper iodide and an inorganic baseselected from the group consisting of potassium carbonate and potassiumphosphate, thereby obtaining the compound represented by formula (AD-2).2. A method for manufacturing a compound represented by formula (AD-2)below:

in formula (AD-2), p denotes an integer between 0 and 3; R¹ groups eachindependently denote a group arbitrarily selected from among a halogenatom, a cyano group, a C₁₋₆ alkyl group, a C₃₋₈ cycloalkyl group, ahalogenated C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₁₋₆ alkoxy group,a C₁₋₆ alkoxy-C₂₋₆ alkyl group, a hydroxy-C₁₋₆ alkyl group and a C₂₋₇alkanoyl group; R² denotes a C₁₋₆ alkyl group; R³ denotes a grouparbitrarily selected from among a hydrogen atom and a fluorine atom; andring A group represented by formula (II):

denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarilyselected from among a thiazol-2-yl group, a thiazol-4-yl group, a1-methyl-1H-imidazol-4-yl group, a 1,3,4-thiadiazol-2-yl group, a1,2,4-thiadiazol-5-yl group, a pyridin-2-yl group, a pyridazin-3-ylgroup, a pyrimidin-2-yl group, a pyrimidin-4-yl group and a pyrazin-2-ylgroup, the manufacturing method comprising stages in which a compoundrepresented by formula (ET-1):

in formula (ET-1), p, R¹, R² and ring A group represented by formula(II) are defined in the same way as for formula (AD-2); R^(D) denotes agroup arbitrarily selected from among a C₁₋₆ alkyl group, a C₆₋₁₄ arylgroup and a C₇₋₂₀ aralkyl group; and an aqueous ammonia solution arereacted with each other at a temperature between 0° C. and a temperatureat which the reaction solution refluxes, thereby obtaining a compoundrepresented by formula (AD-1):

in formula (AD-1), p, R¹, R² and ring A group represented by formula(II) are defined in the same way as for formula (AD-2), and the compoundrepresented by formula (AD-1) and a 2-amino-4-iodopyridine derivativerepresented by formula (PY-1):

in formula (PY-1), R³ denotes a group arbitrarily selected from among ahydrogen atom and a fluorine atom are reacted with each other using asolvent which does not take part in the reaction and which is selectedfrom the group consisting of 1,4-dioxane, tetrahydrofuran and1,2-dimethoxyethane at a temperature between 0° C. and a temperature atwhich the solvent refluxes in the presence ofN,N-dimethyl-1,2-ethanediamine, copper iodide and an inorganic baseselected from the group consisting of potassium carbonate and potassiumphosphate, thereby obtaining the compound represented by formula (AD-2).3. A compound represented by formula (AD-1) below:

in formula (AD-1), p denotes an integer between 0 and 3; R¹ groups eachindependently denote a group arbitrarily selected from among a halogenatom, a cyano group, a C₁₋₆alkyl group, a C₃₋₈ cycloalkyl group, ahalogenated C₁₋₆alkyl group, a C₂₋₆ alkenyl group, a C₁₋₆ alkoxy group,a C₁₋₆ alkoxy-C₁₋₆ alkyl group, a hydroxy-C₁₋₆ alkyl group and a C₂₋₇alkanoyl group; R² denotes a C₁₋₆ alkyl group; and ring A grouprepresented by formula (II):

denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarilyselected from among a thiazol-2-yl group, a thiazol-4-yl group, a1-methyl-1H-imidazol-4-yl group, a 1,3,4-thiadiazol-2-yl group, a1,2,4-thiadiazol-5-yl group, a pyridin-2-yl group, a pyridazin-3-ylgroup, a pyrimidin-2-yl group, a pyrimidin-4-yl group and a pyrazin-2-ylgroup, or a salt of the compound, or a solvate of the compound or salt.4. The compound of claim 3, wherein the compound is any one ofintermediate compounds below, or a salt of the intermediate compound, ora solvate of the intermediate compound or salt:4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide;1-methyl-4-(2-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxamide;4-(5-fluoro-2-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide;and1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxamide.5. A compound represented by formula (AD-2) below:

in formula (AD-2), p denotes an integer between 0 and 3; R¹ groups eachindependently denote a group arbitrarily selected from among a halogenatom, a cyano group, a C₁₋₆ alkyl group, a C₃₋₈ cycloalkyl group, ahalogenated C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₁₋₆ alkoxy group,a C₁₋₆ alkoxy-C₁₋₆ alkyl group, a hydroxy-C₁₋₆ alkyl group and a C₂₋₇alkanoyl group; R² denotes a C₁₋₆ alkyl group; R³ denotes a grouparbitrarily selected from among a hydrogen atom and a fluorine atom; andring A group represented by formula (II):

denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarilyselected from among a thiazol-2-yl group, a thiazol-4-yl group, a1-methyl-1H-imidazol-4-yl group, a 1,3,4-thiadiazol-2-yl group, a1,2,4-thiadiazol-5-yl group, a pyridin-2-yl group, a pyridazin-3-ylgroup, a pyrimidin-2-yl group, a pyrimidin-4-yl group and a pyrazin-2-ylgroup, or a salt of the compound, or a solvate of the compound or salt.6. The compound of claim 5, wherein the compound is any one ofintermediate compounds below, or a salt of the intermediate compound, ora solvate of the intermediate compound or salt:N-(2-amino-5-fluoropyridin-4-yl)-4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide;N-(2-amino-5-fluoropyridin-4-yl)-4-(2-methylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide;andN-(2-amino-5-fluoropyridin-4-yl)-4-(5-fluoro-2-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide;N-(2-amino-5-fluoropyridin-4-yl)-4-(4-(trifluoromethyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxamide.